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Heart, Lung and Circulation

Toll-Like Receptor 3 in Cardiovascular Diseases

  • Author Footnotes
    # Chunying Zhuang and Riken Chen contributed equally to this work.
    Chunying Zhuang
    Footnotes
    # Chunying Zhuang and Riken Chen contributed equally to this work.
    Affiliations
    China State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    First Clinical School, Guangzhou Medical University, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    # Chunying Zhuang and Riken Chen contributed equally to this work.
    Riken Chen
    Footnotes
    # Chunying Zhuang and Riken Chen contributed equally to this work.
    Affiliations
    China State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
    Search for articles by this author
  • Zhenzhen Zheng
    Affiliations
    Department of Respiration, The Second Affiliated Hospital of Guangdong Medical University, Guangzhou, China
    Search for articles by this author
  • Jianmin Lu
    Affiliations
    China State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
    Search for articles by this author
  • Cheng Hong
    Correspondence
    Corresponding author at: State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, Guangdong Province, 510010, China
    Affiliations
    China State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    # Chunying Zhuang and Riken Chen contributed equally to this work.
Published:March 30, 2022DOI:https://doi.org/10.1016/j.hlc.2022.02.012
      Toll-like receptor 3 (TLR3) is an important member of the innate immune response receptor toll-like receptors (TLRs) family, which plays a vital role in regulating immune response, promoting the maturation and differentiation of immune cells, and participating in the response of pro-inflammatory factors. TLR3 is activated by pathogen-associated molecular patterns and damage-associated molecular patterns, which support the pathophysiology of many diseases related to inflammation. An increasing number of studies have confirmed that TLR3, as a crucial medium of innate immunity, participates in the occurrence and development of cardiovascular diseases (CVDs) by regulating the transcription and translation of various cytokines, thus affecting the structure and physiological function of resident cells in the cardiovascular system, including vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts and macrophages. The dysfunction and structural damage of vascular endothelial cells and proliferation of vascular smooth muscle cells are the key factors in the occurrence of vascular diseases such as pulmonary arterial hypertension, atherosclerosis, myocardial hypertrophy, myocardial infarction, ischaemia/reperfusion injury, and heart failure. Meanwhile, cardiomyocytes, fibroblasts, and macrophages are involved in the development of CVDs. Therefore, the purpose of this review was to explore the latest research published on TLR3 in CVDs and discuss current understanding of potential mechanisms by which TLR3 contributes to CVDs. Even though TLR3 is a developing area, it has strong treatment potential as an immunomodulator and deserves further study for clinical translation.

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      References

        • Vijay K.
        Toll-like receptors in immunity and inflammatory diseases: Past, present, and future.
        Int Immunopharmacol. 2018; 59: 391-412https://doi.org/10.1016/j.intimp.2018.03.002
        • Patra M.C.
        • Choi S.
        Recent progress in the development of toll-like receptor (TLR) antagonists.
        Expert Opin Ther Pat. 2016; 26: 719-730https://doi.org/10.1080/13543776.2016.1185415
        • Vidya M.K.
        • Kumar V.G.
        • Sejian V.
        • Bagath M.
        • Krishnan G.
        • Bhatta R.
        Toll-like receptors: Significance, ligands, signaling pathways, and functions in mammals.
        Int Rev Immunol. 2018; 37: 20-36
        • Kawai T.
        • Akira S.
        The role of pattern-recognition receptors in innate immunity: update on toll-like receptors.
        Nat Immunol. 2010; 11: 373-384
        • Asami J.
        • Shimizu T.
        Structural and functional understanding of the toll-like receptors.
        Protein Sci. 2021; 30: 761-772
        • Liu L.
        • Botos I.
        • Wang Y.
        • Leonard J.N.
        • Shiloach J.
        • Segal D.M.
        • et al.
        Structural basis of toll-like receptor 3 signaling with double-stranded RNA.
        Science. 2008; 320: 379-381
        • Adamczak D.M.
        The role of toll-like receptors and vitamin D in cardiovascular diseases: A review.
        Int J Mol Sci. 2017; 18: 2252
        • Goulopoulou S.
        • McCarthy C.G.
        • Webb R.C.
        Toll-like receptors in the vascular system: Sensing the dangers within.
        Pharmacol Rev. 2016; 68: 142-167
        • Tang D.
        • Kang R.
        • Coyne C.B.
        • Zeh H.J.
        • Lotze M.T.
        PAMPs and DAMPs: signal 0s that spur autophagy and immunity.
        Immunol Rev. 2012; 249: 158-175
        • Qian C.
        • Cao X.
        Regulation of toll-like receptor signaling pathways in innate immune responses.
        Ann N Y Acad Sci. 2013; 1283: 67-74
        • Salvador B.
        • Arranz A.
        • Francisco S.
        • Cordoba L.
        • Punzon C.
        • Llamas M.A.
        • et al.
        Modulation of endothelial function by toll-like receptors.
        Pharmacol Res. 2016; 108: 46-56
        • Wang Y.
        • Song E.
        • Bai B.
        • Vanhoutte P.M.
        Toll-like receptors mediating vascular malfunction: Lessons from receptor subtypes.
        Pharmacol Ther. 2016; 158: 91-100
        • Farkas D.
        • Thompson A.A.R.
        • Bhagwani A.R.
        • Hultman S.
        • Ji H.
        • Kotha N.
        • et al.
        Toll-like receptor 3 is a therapeutic target for pulmonary hypertension.
        Am J Respir Crit Care Med. 2019; 199: 199-210
        • Gui L.
        • Zhu J.
        • Lu X.
        • Sims S.M.
        • Lu W.Y.
        • Stathopulos P.B.
        • et al.
        S-Nitrosylation of STIM1 by neuronal nitric oxide synthase inhibits store-operated Ca(2+) entry.
        J Mol Biol. 2018; 430: 1773-1785
        • Li B.
        • Xia Y.
        • Hu B.
        Infection and atherosclerosis: TLR-dependent pathways.
        Cell Mol Life Sci. 2020; 77: 2751-2769
        • Bugge M.
        • Bergstrom B.
        • Eide O.K.
        • Solli H.
        • Kjonstad I.F.
        • Stenvik J.
        • et al.
        Surface toll-like receptor 3 expression in metastatic intestinal epithelial cells induces inflammatory cytokine production and promotes invasiveness.
        J Biol Chem. 2017; 292: 15408-15425
        • Chen C.Y.
        • Shih Y.C.
        • Hung Y.F.
        • Hsueh Y.P.
        Beyond defense: Regulation of neuronal morphogenesis and brain functions via toll-like receptors.
        J Biomed Sci. 2019; 26: 90
        • Fang F.
        • Ooka K.
        • Sun X.
        • Shah R.
        • Bhattacharyya S.
        • Wei J.
        • et al.
        A synthetic TLR3 ligand mitigates profibrotic fibroblast responses by inducing autocrine IFN signaling.
        J Immunol. 2013; 191: 2956-2966
        • Kulka M.
        • Alexopoulou L.
        • Flavell R.A.
        • Metcalfe D.D.
        Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3.
        J Allergy Clin Immunol. 2004; 114: 174-182
        • Agier J.
        • Zelechowska P.
        • Kozlowska E.
        • Brzezinska-Blaszczyk E.
        Expression of surface and intracellular toll-like receptors by mature mast cells.
        Cent Eur J Immunol. 2016; 41: 333-338
        • Chattopadhyay S.
        • Sen G.C.
        dsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects.
        J Interferon Cytokine Res. 2014; 34: 427-436
        • Grelier A.
        • Cras A.
        • Balitrand N.
        • Delmau C.
        • Lecourt S.
        • Lepelletier Y.
        • et al.
        Toll-like receptor 3 regulates cord blood-derived endothelial cell function in vitro and in vivo.
        Angiogenesis. 2013; 16: 821-836
        • Matsumoto M.
        • Oshiumi H.
        • Seya T.
        Antiviral responses induced by the TLR3 pathway.
        Rev Med Virol. 2011; 21: 67-77
        • Zhao J.
        • Huang X.
        • McLeod P.
        • Jiang J.
        • Liu W.
        • Haig A.
        • et al.
        Toll-like receptor 3 is an endogenous sensor of cell death and a potential target for induction of long-term cardiac transplant survival.
        Am J Transplant. 2021; 21: 3268-3279
        • Matsumoto M.
        • Takeda Y.
        • Seya T.
        Targeting toll-like receptor 3 in dendritic cells for cancer immunotherapy.
        Expert Opin Biol Ther. 2020; 20: 937-946
        • Soto J.A.
        • Galvez N.M.S.
        • Andrade C.A.
        • Pacheco G.A.
        • Bohmwald K.
        • Berrios R.V.
        • et al.
        The role of dendritic cells during infections caused by highly prevalent viruses.
        Front Immunol. 2020; 11: 1513
        • Piliponsky A.M.
        • Romani L.
        The contribution of mast cells to bacterial and fungal infection immunity.
        Immunol Rev. 2018; 282: 188-197
        • Marshall J.S.
        • Portales-Cervantes L.
        • Leong E.
        Mast cell responses to viruses and pathogen products.
        Int J Mol Sci. 2019; 20: 4241
        • Alexopoulou L.
        • Holt A.C.
        • Medzhitov R.
        • Flavell R.A.
        Recognition of double-stranded RNA and activation of NF-kappaB by toll-like receptor 3.
        Nature. 2001; 413: 732-738
        • Lai Y.
        • Yi G.
        • Chen A.
        • Bhardwaj K.
        • Tragesser B.J.
        • Rodrigo A.V.
        • et al.
        Viral double-strand RNA-binding proteins can enhance innate immune signaling by toll-like Receptor 3.
        PLoS One. 2011; 6e25837
        • Bernard J.J.
        • Cowing-Zitron C.
        • Nakatsuji T.
        • Muehleisen B.
        • Muto J.
        • Borkowski A.W.
        • et al.
        Ultraviolet radiation damages self-noncoding RNA and is detected by TLR3.
        Nat Med. 2012; 18: 1286-1290
        • Zhang S.Y.
        • Jouanguy E.
        • Ugolini S.
        • Smahi A.
        • Elain G.
        • Romero P.
        • et al.
        TLR3 deficiency in patients with herpes simplex encephalitis.
        Science. 2007; 317: 1522-1527
        • Lin Q.
        • Li M.
        • Fang D.
        • Fang J.
        • Su S.B.
        The essential roles of Toll-like receptor signaling pathways in sterile inflammatory diseases.
        Int Immunopharmacol. 2011; 11: 1422-1432
        • Gong T.
        • Liu L.
        • Jiang W.
        • Zhou R.
        DAMP-sensing receptors in sterile inflammation and inflammatory diseases.
        Nat Rev Immunol. 2020; 20: 95-112
        • Yu L.
        • Wang L.
        • Chen S.
        Endogenous toll-like receptor ligands and their biological significance.
        J Cell Mol Med. 2010; 14: 2592-2603
        • Cavassani K.A.
        • Ishii M.
        • Wen H.
        • Schaller M.A.
        • Lincoln P.M.
        • Lukacs N.W.
        • et al.
        TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events.
        J Exp Med. 2008; 205: 2609-2621
        • Majer O.
        • Liu B.
        • Barton G.M.
        Nucleic acid-sensing TLRs: trafficking and regulation.
        Curr Opin Immunol. 2017; 44: 26-33
        • Lind N.A.
        • Rael V.E.
        • Pestal K.
        • Liu B.
        • Barton G.M.
        Regulation of the nucleic acid-sensing Toll-like receptors.
        Nat Rev Immunol. 2021; https://doi.org/10.1038/s41577-021-00577-0
        • Lande R.
        • Gregorio J.
        • Facchinetti V.
        • Chatterjee B.
        • Wang Y.H.
        • Homey B.
        Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide.
        Nature. 2007; 449: 564-569
        • Barton G.M.
        • Kagan J.C.
        A cell biological view of Toll-like receptor function: regulation through compartmentalization.
        Nat Rev Immunol. 2009; 9: 535-542
        • Pelka K.
        • Bertheloot D.
        • Reimer E.
        • Phulphagar K.
        • Schmidt S.V.
        • Christ A.
        • et al.
        The chaperone UNC93B1 regulates toll-like receptor stability independently of endosomal TLR transport.
        Immunity. 2018; 48: 911-922.e7
        • Salio M.
        • Cerundolo V.
        Viral immunity: cross-priming with the help of TLR3.
        Curr Biol. 2005; 15: R336-R339
        • Itoh K.
        • Watanabe A.
        • Funami K.
        • Seya T.
        • Matsumoto M.
        The clathrin-mediated endocytic pathway participates in dsRNA-induced IFN-beta production.
        J Immunol. 2008; 181: 5522-5529
        • Takahashi T.
        • Kulkarni N.N.
        • Lee E.Y.
        • Zhang L.J.
        • Wong G.C.L.
        • Gallo R.L.
        Cathelicidin promotes inflammation by enabling binding of self-RNA to cell surface scavenger receptors.
        Sci Rep. 2018; 8: 4032
        • Galluzzi L.
        • Green D.R.
        Autophagy-Independent functions of the autophagy machinery.
        Cell. 2019; 177: 1682-1699
        • Hase K.
        • Contu V.R.
        • Kabuta C.
        • Sakai R.
        • Takahashi M.
        • Kataoka N.
        • et al.
        Cytosolic domain of SIDT2 carries an arginine-rich motif that binds to RNA/DNA and is important for the direct transport of nucleic acids into lysosomes.
        Autophagy. 2020; 16: 1974-1988
        • Soreng K.
        • Neufeld T.P.
        • Simonsen A.
        Membrane Trafficking in Autophagy.
        Int Rev Cell Mol Biol. 2018; 336: 1-92
        • Panneerselvam P.
        • Ding J.L.
        Beyond TLR signaling-The role of SARM in antiviral immune defense, apoptosis & development.
        Int Rev Immunol. 2015; 34: 432-444
        • Ullah M.O.
        • Sweet M.J.
        • Mansell A.
        • Kellie S.
        • Kobe B.
        TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target.
        J Leukoc Biol. 2016; 100: 27-45
        • Wang L.
        • Yu K.
        • Zhang X.
        • Yu S.
        Dual functional roles of the MyD88 signaling in colorectal cancer development.
        Biomed Pharmacother. 2018; 107: 177-184
        • Alonso-Perez A.
        • Franco-Trepat E.
        • Guillan-Fresco M.
        • Jorge-Mora A.
        • Lopez V.
        • Pino J.
        • et al.
        Role of Toll-like receptor 4 on osteoblast metabolism and function.
        Front Physiol. 2018; 9: 504
        • Yang Q.
        • Shu H.B.
        Deciphering the pathways to antiviral innate immunity and inflammation.
        Adv Immunol. 2020; 145: 1-36
        • Yang Y.
        • Wang S.Y.
        • Huang Z.F.
        • Zou H.M.
        • Yan B.R.
        • Luo W.W.
        • et al.
        The RNA-binding protein Mex3B is a coreceptor of toll-like receptor 3 in innate antiviral response.
        Cell Res. 2016; 26: 288-303
        • Zhu S.
        • Wang G.
        • Lei X.
        • Flavell R.A.
        Mex3B: a coreceptor to present dsRNA to TLR3.
        Cell Res. 2016; 26: 391-392
        • Yamashita M.
        • Chattopadhyay S.
        • Fensterl V.
        • Saikia P.
        • Wetzel J.L.
        • Sen G.C.
        Epidermal growth factor receptor is essential for toll-like receptor 3 signaling.
        Sci Signal. 2012; 5: ra50
        • Zhong X.
        • Feng L.
        • Xu W.H.
        • Wu X.
        • Ding Y.D.
        • Zhou Y.
        • et al.
        The zinc-finger protein ZFYVE1 modulates TLR3-mediated signaling by facilitating TLR3 ligand binding.
        Cell Mol Immunol. 2020; 17: 741-752
        • Sayed N.
        • Wong W.T.
        • Ospino F.
        • Meng S.
        • Lee J.
        • Jha A.
        • et al.
        Transdifferentiation of human fibroblasts to endothelial cells: role of innate immunity.
        Circulation. 2015; 131: 300-309
        • Tabeta K.
        • Hoebe K.
        • Janssen E.M.
        • Du X.
        • Georgel P.
        • Crozat K.
        • et al.
        The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via toll-like receptors 3, 7 and 9.
        Nat Immunol. 2006; 7: 156-164
        • Kim Y.M.
        • Brinkmann M.M.
        • Paquet M.E.
        • Ploegh H.L.
        UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes.
        Nature. 2008; 452: 234-238
        • Garcia-Cattaneo A.
        • Gobert F.X.
        • Muller M.
        • Toscano F.
        • Flores M.
        • Lescure A.
        • et al.
        Cleavage of Toll-like receptor 3 by cathepsins B and H is essential for signaling.
        Proc Natl Acad Sci U S A. 2012; 109: 9053-9058
        • Leonard J.N.
        • Ghirlando R.
        • Askins J.
        • Bell J.K.
        • Margulies D.H.
        • Davies D.R.
        • et al.
        The TLR3 signaling complex forms by cooperative receptor dimerization.
        Proc Natl Acad Sci U S A. 2008; 105: 258-263
        • Gay N.J.
        • Gangloff M.
        Structure and function of Toll receptors and their ligands.
        Annu Rev Biochem. 2007; 76: 141-165
        • Leonard J.N.
        • Bell J.K.
        • Segal D.M.
        Predicting Toll-like receptor structures and characterizing ligand binding.
        Methods Mol Biol. 2009; 517: 55-67
        • Yamamoto M.
        • Sato S.
        • Mori K.
        • Hoshino K.
        • Takeuchi O.
        • Takeda K.
        • et al.
        Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling.
        J Immunol. 2002; 169: 6668-6672
        • Hacker H.
        • Redecke V.
        • Blagoev B.
        • Kratchmarova I.
        • Hsu L.C.
        • Wang G.G.
        • et al.
        Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6.
        Nature. 2006; 439: 204-207
        • Fitzgerald K.A.
        • McWhirter S.M.
        • Faia K.L.
        • Rowe D.C.
        • Latz E.
        • Golenbock D.T.
        • et al.
        IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.
        Nat Immunol. 2003; 4: 491-496
        • Zhang K.
        • Zhang Y.
        • Xue J.
        • Meng Q.
        • Liu H.
        • Bi C.
        • et al.
        DDX19 inhibits type 1 interferon production by disrupting TBK1-IKKepsilon-IRF3 interactions and promoting TBK1 and IKKepsilon degradation.
        Cell Rep. 2019; 26: 1258-1272.e4
        • Miciak J.
        • Bunz F.
        Long story short: p53 mediates innate immunity.
        Biochim Biophys Acta. 2016; 1865: 220-227
        • Lim K.H.
        • Staudt L.M.
        Toll-like receptor signaling.
        Cold Spring Harb Perspect Biol. 2013; 5a011247
        • Gudkov A.V.
        • Gurova K.V.
        • Komarova E.A.
        Inflammation and p53: A tale of two stresses.
        Genes Cancer. 2011; 2: 503-516
        • Oganesyan G.
        • Saha S.K.
        • Guo B.
        • He J.Q.
        • Shahangian A.
        • Zarnegar B.
        • et al.
        Critical role of TRAF3 in the toll-like receptor-dependent and -independent antiviral response.
        Nature. 2006; 439: 208-211
        • Dabo S.
        • Meurs E.F.
        dsRNA-dependent protein kinase PKR and its role in stress, signaling and HCV infection.
        Viruses. 2012; 4: 2598-2635
        • Kim Y.
        • Park J.
        • Kim S.
        • Kim M.
        • Kang M.G.
        • Kwak C.
        • et al.
        PKR senses nuclear and mitochondrial signals by interacting with endogenous double-stranded RNAs.
        Mol Cell. 2018; 71: 1051-1063.e6
        • Back S.H.
        Roles of the translation initiation factor eIF2alpha phosphorylation in cell structure and function.
        Cell Struct Funct. 2020; 45: 65-76
        • Kashiwagi K.
        • Yokoyama T.
        • Nishimoto M.
        • Takahashi M.
        • Sakamoto A.
        • Yonemochi M.
        • et al.
        Structural basis for eIF2B inhibition in integrated stress response.
        Science. 2019; 364: 495-499
        • Hacker H.
        • Tseng P.H.
        • Karin M.
        Expanding TRAF function: TRAF3 as a tri-faced immune regulator.
        Nat Rev Immunol. 2011; 11: 457-468
        • Owen A.M.
        • Fults J.B.
        • Patil N.K.
        • Hernandez A.
        • Bohannon J.K.
        TLR Agonists as mediators of trained immunity: Mechanistic insight and immunotherapeutic potential to combat infection.
        Front Immunol. 2020; 11622614
        • Jiang Z.
        • Ninomiya-Tsuji J.
        • Qian Y.
        • Matsumoto K.
        • Li X.
        Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol.
        Mol Cell Biol. 2002; 22: 7158-7167
        • Roy A.
        • Srivastava M.
        • Saqib U.
        • Liu D.
        • Faisal S.M.
        • Sugathan S.
        • et al.
        Potential therapeutic targets for inflammation in toll-like receptor 4 (TLR4)-mediated signaling pathways.
        Int Immunopharmacol. 2016; 40: 79-89
        • Napetschnig J.
        • Wu H.
        Molecular basis of NF-kappaB signaling.
        Annu Rev Biophys. 2013; 42: 443-468
        • Jiang Z.
        • Mak T.W.
        • Sen G.
        • Li X.
        Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta.
        Proc Natl Acad Sci U S A. 2004; 101: 3533-3538
        • Jiang Z.
        • Zamanian-Daryoush M.
        • Nie H.
        • Silva A.M.
        • Williams B.R.
        • Li X.
        Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR.
        J Biol Chem. 2003; 278: 16713-16719
        • Morrison D.K.
        MAP kinase pathways.
        Cold Spring Harb Perspect Biol. 2012; 4a011254
        • Takeuchi O.
        • Akira S.
        Pattern recognition receptors and inflammation.
        Cell. 2010; 140: 805-820
        • Xu G.
        • Xia Z.
        • Deng F.
        • Liu L.
        • Wang Q.
        • Yu Y.
        • et al.
        Inducible LGALS3BP/90K activates antiviral innate immune responses by targeting TRAF6 and TRAF3 complex.
        PLoS Pathog. 2019; 15e1008002
        • Ghosh T.K.
        • Mickelson D.J.
        • Fink J.
        • Solberg J.C.
        • Inglefield J.R.
        • Hook D.
        • et al.
        Toll-like receptor (TLR) 2-9 agonists-induced cytokines and chemokines: I. Comparison with T cell receptor-induced responses.
        Cell Immunol. 2006; 243: 48-57
        • Fitzgerald K.A.
        • Kagan J.C.
        Toll-like receptors and the control of immunity.
        Cell. 2020; 180: 1044-1066
        • Sandig H.
        • Bulfone-Paus S.
        TLR signaling in mast cells: common and unique features.
        Front Immunol. 2012; 3: 185
        • Shlomovitz I.
        • Zargrian S.
        • Gerlic M.
        Mechanisms of RIPK3-induced inflammation.
        Immunol Cell Biol. 2017; 95: 166-172
        • He S.
        • Liang Y.
        • Shao F.
        • Wang X.
        Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway.
        Proc Natl Acad Sci U S A. 2011; 108: 20054-20059
        • Blackwell T.K.
        • Sewell A.K.
        • Wu Z.
        • Han M.
        TOR Signaling in Caenorhabditis elegans development, metabolism, and aging.
        Genetics. 2019; 213: 329-360
        • Liberati N.T.
        • Fitzgerald K.A.
        • Kim D.H.
        • Feinbaum R.
        • Golenbock D.T.
        • Ausubel F.M.
        Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response.
        Proc Natl Acad Sci U S A. 2004; 101: 6593-6598
        • Carty M.
        • Goodbody R.
        • Schroder M.
        • Stack J.
        • Moynagh P.N.
        • Bowie A.G.
        The human adaptor SARM negatively regulates adaptor protein TRIF-dependent toll-like receptor signaling.
        Nat Immunol. 2006; 7: 1074-1081
        • Carty M.
        • Bowie A.G.
        SARM: From immune regulator to cell executioner.
        Biochem Pharmacol. 2019; 161: 52-62
        • O’Neill L.A.
        • Bowie A.G.
        The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling.
        Nat Rev Immunol. 2007; 7: 353-364
        • Carty M.
        • Kearney J.
        • Shanahan K.A.
        • Hams E.
        • Sugisawa R.
        • Connolly D.
        • et al.
        Cell survival and cytokine release after inflammasome activation is regulated by the toll-IL-1R protein SARM.
        Immunity. 2019; 50: 1412-1424.e6
        • Lilly B.
        We have contact: endothelial cell-smooth muscle cell interactions.
        Physiology (Bethesda). 2014; 29: 234-241
        • Bhagwani A.
        • Thompson A.A.R.
        • Farkas L.
        When innate immunity meets angiogenesis-the role of toll-like receptors in endothelial cells and pulmonary hypertension.
        Front Med (Lausanne). 2020; 7: 352
        • Pober J.S.
        • Sessa W.C.
        Evolving functions of endothelial cells in inflammation.
        Nat Rev Immunol. 2007; 7: 803-815
        • Sehnert B.
        • Burkhardt H.
        • Wessels J.T.
        • Schroder A.
        • May M.J.
        • Vestweber D.
        • et al.
        NF-kappaB inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF-kappaB in immune-mediated diseases.
        Proc Natl Acad Sci U S A. 2013; 110: 16556-16561
        • Tewalt E.F.
        • Cohen J.N.
        • Rouhani S.J.
        • Engelhard V.H.
        Lymphatic endothelial cells - key players in regulation of tolerance and immunity.
        Front Immunol. 2012; 3: 305
        • Al-Soudi A.
        • Kaaij M.H.
        • Tas S.W.
        Endothelial cells: From innocent bystanders to active participants in immune responses.
        Autoimmun Rev. 2017; 16: 951-962
        • Evrard S.M.
        • Lecce L.
        • Michelis K.C.
        • Nomura-Kitabayashi A.
        • Pandey G.
        • Purushothaman K.R.
        • et al.
        Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability.
        Nat Commun. 2016; 7: 11853
        • O’Neill L.
        • Molloy E.S.
        The role of toll like receptors in giant cell arteritis.
        Rheumatology (Oxford). 2016; 55: 1921-1931
        • Pryshchep O.
        • Ma-Krupa W.
        • Younge B.R.
        • Goronzy J.J.
        • Weyand C.M.
        Vessel-specific Toll-like receptor profiles in human medium and large arteries.
        Circulation. 2008; 118: 1276-1284
        • Frismantiene A.
        • Philippova M.
        • Erne P.
        • Resink T.J.
        Smooth muscle cell-driven vascular diseases and molecular mechanisms of VSMC plasticity.
        Cell Signal. 2018; 52: 48-64
        • Dejana E.
        • Hirschi K.K.
        • Simons M.
        The molecular basis of endothelial cell plasticity.
        Nat Commun. 2017; 8: 14361
        • Farina G.
        • York M.
        • Collins C.
        • Lafyatis R.
        dsRNA activation of endothelin-1 and markers of vascular activation in endothelial cells and fibroblasts.
        Ann Rheum Dis. 2011; 70: 544-550
        • Tsaousi A.
        • Williams H.
        • Lyon C.A.
        • Taylor V.
        • Swain A.
        • Johnson J.L.
        • et al.
        Wnt4/beta-catenin signaling induces VSMC proliferation and is associated with intimal thickening.
        Circ Res. 2011; 108: 427-436
        • Paulin R.
        • Michelakis E.D.
        The metabolic theory of pulmonary arterial hypertension.
        Circ Res. 2014; 115: 148-164
        • Rodriguez-Pascual F.
        • Busnadiego O.
        • Lagares D.
        • Lamas S.
        Role of endothelin in the cardiovascular system.
        Pharmacol Res. 2011; 63: 463-472
        • Li Y.Q.
        • Ngo A.
        • Hoffmann P.
        • Ferrante A.
        • Hii C.S.
        Regulation of endothelial cell survival and death by the MAP kinase/ERK kinase kinase 3 - glyceraldehyde-3-phosphate dehydrogenase signaling axis.
        Cell Signal. 2019; 58: 20-33
        • Bennett M.R.
        • Sinha S.
        • Owens G.K.
        Vascular smooth muscle cells in atherosclerosis.
        Circ Res. 2016; 118: 692-702
        • Brown M.A.
        • Jones W.K.
        NF-kappaB action in sepsis: the innate immune system and the heart.
        Front Biosci. 2004; 9: 1201-1217
        • Commins S.P.
        • Borish L.
        • Steinke J.W.
        Immunologic messenger molecules: cytokines, interferons, and chemokines.
        J Allergy Clin Immunol. 2010; 125: S53-S72
        • Moser B.
        • Wolf M.
        • Walz A.
        • Loetscher P.
        Chemokines: multiple levels of leukocyte migration control.
        Trends Immunol. 2004; 25: 75-84
        • Wang X.
        • Ha T.
        • Liu L.
        • Hu Y.
        • Kao R.
        • Kalbfleisch J.
        • et al.
        TLR3 mediates repair and regeneration of damaged neonatal heart through glycolysis dependent YAP1 regulated miR-152 expression.
        Cell Death Differ. 2018; 25: 966-982
        • Chen E.
        • Chen C.
        • Niu Z.
        • Gan L.
        • Wang Q.
        • Li M.
        • et al.
        Poly(I:C) preconditioning protects the heart against myocardial ischemia/reperfusion injury through TLR3/PI3K/Akt-dependent pathway.
        Signal Transduct Target Ther. 2020; 5: 216
        • Souders C.A.
        • Bowers S.L.
        • Baudino T.A.
        Cardiac fibroblast: the renaissance cell.
        Circ Res. 2009; 105: 1164-1176
        • Travers J.G.
        • Kamal F.A.
        • Robbins J.
        • Yutzey K.E.
        • Blaxall B.C.
        Cardiac fibrosis: The fibroblast awakens.
        Circ Res. 2016; 118: 1021-1040
        • Meng S.
        • Lu J.
        • Chanda P.K.
        • Owusu I.
        • Chen K.
        • Cooke J.P.
        Reservoir of fibroblasts promotes recovery from limb ischemia.
        Circulation. 2020; 142: 1647-1662
        • Zhang Q.
        • Bastard P.
        • Liu Z.
        • Le Pen J.
        • Moncada-Velez M.
        • Chen J.
        • et al.
        Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.
        Science. 2020; 370eabd4570
        • Zou L.
        • Feng Y.
        • Li Y.
        • Zhang M.
        • Chen C.
        • Cai J.
        • et al.
        Complement factor B is the downstream effector of TLRs and plays an important role in a mouse model of severe sepsis.
        J Immunol. 2013; 191: 5625-5635
        • Deng T.
        • Feng X.
        • Liu P.
        • Yan K.
        • Chen Y.
        • Han D.
        Toll-like receptor 3 activation differentially regulates phagocytosis of bacteria and apoptotic neutrophils by mouse peritoneal macrophages.
        Immunol Cell Biol. 2013; 91: 52-59
        • Rabinovitch M.
        Molecular pathogenesis of pulmonary arterial hypertension.
        J Clin Invest. 2012; 122: 4306-4313
        • Rabinovitch M.
        • Guignabert C.
        • Humbert M.
        • Nicolls M.R.
        Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension.
        Circ Res. 2014; 115: 165-175
        • Good R.B.
        • Gilbane A.J.
        • Trinder S.L.
        • Denton C.P.
        • Coghlan G.
        • Abraham D.J.
        • et al.
        Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension.
        Am J Pathol. 2015; 185: 1850-1858
        • Raymond M.A.
        • Desormeaux A.
        • Laplante P.
        • Vigneault N.
        • Filep J.G.
        • Landry K.
        • et al.
        Apoptosis of endothelial cells triggers a caspase-dependent anti-apoptotic paracrine loop active on VSMC.
        FASEB J. 2004; 18: 705-707
        • Macchia A.
        • Marchioli R.
        • Tognoni G.
        • Scarano M.
        • Marfisi R.
        • Tavazzi L.
        • et al.
        Systematic review of trials using vasodilators in pulmonary arterial hypertension: why a new approach is needed.
        Am Heart J. 2010; 159: 245-257
        • Stacher E.
        • Graham B.B.
        • Hunt J.M.
        • Gandjeva A.
        • Groshong S.D.
        • McLaughlin V.V.
        • et al.
        Modern age pathology of pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2012; 186: 261-272
        • Cole J.E.
        • Navin T.J.
        • Cross A.J.
        • Goddard M.E.
        • Alexopoulou L.
        • Mitra A.T.
        • et al.
        Unexpected protective role for toll-like receptor 3 in the arterial wall.
        Proc Natl Acad Sci U S A. 2011; 108: 2372-2377
        • Asdonk T.
        • Steinmetz M.
        • Krogmann A.
        • Strocker C.
        • Lahrmann C.
        • Motz I.
        • et al.
        MDA-5 activation by cytoplasmic double-stranded RNA impairs endothelial function and aggravates atherosclerosis.
        J Cell Mol Med. 2016; 20: 1696-1705
        • Palchetti S.
        • Starace D.
        • De Cesaris P.
        • Filippini A.
        • Ziparo E.
        • Riccioli A.
        Transfected poly(I:C) activates different dsRNA receptors, leading to apoptosis or immunoadjuvant response in androgen-independent prostate cancer cells.
        J Biol Chem. 2015; 290: 5470-5483
        • Chaudhary K.R.
        • Taha M.
        • Cadete V.J.
        • Godoy R.S.
        • Stewart D.J.
        Proliferative versus degenerative paradigms in pulmonary arterial hypertension: Have we put the cart before the horse?.
        Circ Res. 2017; 120: 1237-1239
        • Farkas D.
        • Alhussaini A.A.
        • Kraskauskas D.
        • Kraskauskiene V.
        • Cool C.D.
        • Nicolls M.R.
        • et al.
        Nuclear factor kappaB inhibition reduces lung vascular lumen obliteration in severe pulmonary hypertension in rats.
        Am J Respir Cell Mol Biol. 2014; 51: 413-425
        • Tian W.
        • Jiang X.
        • Tamosiuniene R.
        • Sung Y.K.
        • Qian J.
        • Dhillon G.
        • et al.
        Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension.
        Sci Transl Med. 2013; 5200ra117
        • Tuder R.M.
        • Archer S.L.
        • Dorfmuller P.
        • Erzurum S.C.
        • Guignabert C.
        • Michelakis E.
        • et al.
        Relevant issues in the pathology and pathobiology of pulmonary hypertension.
        J Am Coll Cardiol. 2013; 62: D4-D12
        • Galie N.
        • Manes A.
        • Branzi A.
        The endothelin system in pulmonary arterial hypertension.
        Cardiovasc Res. 2004; 61: 227-237
        • Byun J.S.
        • Suh Y.G.
        • Yi H.S.
        • Lee Y.S.
        • Jeong W.I.
        Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice.
        J Hepatol. 2013; 58: 342-349
        • Ito T.
        • Okada T.
        • Miyashita H.
        • Nomoto T.
        • Nonaka-Sarukawa M.
        • Uchibori R.
        • et al.
        Interleukin-10 expression mediated by an adeno-associated virus vector prevents monocrotaline-induced pulmonary arterial hypertension in rats.
        Circ Res. 2007; 101: 734-741
        • Krishnamurthy P.
        • Rajasingh J.
        • Lambers E.
        • Qin G.
        • Losordo D.W.
        • Kishore R.
        IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR.
        Circ Res. 2009; 104: e9-e18
        • Zimmer S.
        • Steinmetz M.
        • Asdonk T.
        • Motz I.
        • Coch C.
        • Hartmann E.
        • et al.
        Activation of endothelial toll-like receptor 3 impairs endothelial function.
        Circ Res. 2011; 108: 1358-1366
        • Campanella G.S.
        • Grimm J.
        • Manice L.A.
        • Colvin R.A.
        • Medoff B.D.
        • Wojtkiewicz G.R.
        • et al.
        Oligomerization of CXCL10 is necessary for endothelial cell presentation and in vivo activity.
        J Immunol. 2006; 177: 6991-6998
        • Simonini A.
        • Moscucci M.
        • Muller D.W.
        • Bates E.R.
        • Pagani F.D.
        • Burdick M.D.
        • et al.
        IL-8 is an angiogenic factor in human coronary atherectomy tissue.
        Circulation. 2000; 101: 1519-1526
        • Yang S.
        • Lian G.
        ROS and diseases: role in metabolism and energy supply.
        Mol Cell Biochem. 2020; 467: 1-12
        • Zorov D.B.
        • Juhaszova M.
        • Sollott S.J.
        Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release.
        Physiol Rev. 2014; 94: 909-950
        • Huang L.Y.
        • Stuart C.
        • Takeda K.
        • D’Agnillo F.
        • Golding B.
        Poly(I:C) induces human lung endothelial barrier dysfunction by disrupting tight junction expression of Claudin-5.
        PLoS One. 2016; 11e0160875
        • George P.M.
        • Badiger R.
        • Shao D.
        • Edwards M.R.
        • Wort S.J.
        • Paul-Clark M.J.
        • et al.
        Viral toll-like receptor activation of pulmonary vascular smooth muscle cells results in endothelin-1 generation; relevance to pathogenesis of pulmonary arterial hypertension.
        Biochem Biophys Res Commun. 2012; 426: 486-491
        • Gao Y.
        • Chen T.
        • Raj J.U.
        Endothelial and smooth muscle cell interactions in the pathobiology of pulmonary hypertension.
        Am J Respir Cell Mol Biol. 2016; 54: 451-460
        • Yang X.
        • Murthy V.
        • Schultz K.
        • Tatro J.B.
        • Fitzgerald K.A.
        • Beasley D.
        Toll-like receptor 3 signaling evokes a proinflammatory and proliferative phenotype in human vascular smooth muscle cells.
        Am J Physiol Heart Circ Physiol. 2006; 291: H2334-H2343
        • Wang J.
        • Tian X.T.
        • Peng Z.
        • Li W.Q.
        • Cao Y.Y.
        • Li Y.
        • et al.
        HMGB1/TLR4 promotes hypoxic pulmonary hypertension via suppressing BMPR2 signaling.
        Vascul Pharmacol. 2019; 117: 35-44
        • Wang H.
        • Jing Z.C.
        Inflammation and cardiovascular diseases.
        Chronic Dis Transl Med. 2020; 6: 215-218
        • Pothineni N.V.K.
        • Subramany S.
        • Kuriakose K.
        • Shirazi L.F.
        • Romeo F.
        • Shah P.K.
        • et al.
        Infections, atherosclerosis, and coronary heart disease.
        Eur Heart J. 2017; 38: 3195-3201
        • Zhu Y.
        • Xian X.
        • Wang Z.
        • Bi Y.
        • Chen Q.
        • Han X.
        • et al.
        Research progress on the relationship between atherosclerosis and inflammation.
        biomolecules. 2018; 8: 80
        • Charo I.F.
        • Taub R.
        Anti-inflammatory therapeutics for the treatment of atherosclerosis.
        Nat Rev Drug Discov. 2011; 10: 365-376
        • Kapelouzou A.
        • Giaglis S.
        • Peroulis M.
        • Katsimpoulas M.
        • Moustardas P.
        • Aravanis C.V.
        • et al.
        Overexpression of toll-like receptors 2, 3, 4, and 8 is correlated to the vascular atherosclerotic process in the hyperlipidemic rabbit model: The effect of statin treatment.
        J Vasc Res. 2017; 54: 156-169
        • Lai L.
        • Reineke E.
        • Hamilton D.J.
        • Cooke J.P.
        Glycolytic switch is required for transdifferentiation to endothelial lineage.
        Circulation. 2019; 139: 119-133
        • Baiersdorfer M.
        • Schwarz M.
        • Seehafer K.
        • Lehmann C.
        • Heit A.
        • Wagner H.
        • et al.
        Toll-like receptor 3 mediates expression of clusterin/apolipoprotein J in vascular smooth muscle cells stimulated with RNA released from necrotic cells.
        Exp Cell Res. 2010; 316: 3489-3500
        • Dahl S.
        • Cerps S.
        • Rippe C.
        • Sward K.
        • Uller L.
        • Svensson D.
        • et al.
        Human host defense peptide LL-37 facilitates double-stranded RNA pro-inflammatory signaling through up-regulation of TLR3 expression in vascular smooth muscle cells.
        Inflamm Res. 2022; 69: 579-588
        • Lundberg A.M.
        • Ketelhuth D.F.
        • Johansson M.E.
        • Gerdes N.
        • Liu S.
        • Yamamoto M.
        • et al.
        Toll-like receptor 3 and 4 signalling through the TRIF and TRAM adaptors in haematopoietic cells promotes atherosclerosis.
        Cardiovasc Res. 2013; 99: 364-373
        • Feingold K.R.
        • Kazemi M.R.
        • Magra A.L.
        • McDonald C.M.
        • Chui L.G.
        • Shigenaga J.K.
        • et al.
        ADRP/ADFP and Mal1 expression are increased in macrophages treated with TLR agonists.
        Atherosclerosis. 2010; 209: 81-88
        • Watanabe T.
        • Nishio K.
        • Kanome T.
        • Matsuyama T.A.
        • Koba S.
        • Sakai T.
        • et al.
        Impact of salusin-alpha and -beta on human macrophage foam cell formation and coronary atherosclerosis.
        Circulation. 2008; 117: 638-648
        • Liu L.
        • He H.
        • Liang R.
        • Yi H.
        • Meng X.
        • Chen Z.
        • et al.
        ROS-inducing micelles sensitize tumor-associated macrophages to TLR3 stimulation for potent immunotherapy.
        Biomacromolecules. 2018; 19: 2146-2155
        • Heller E.A.
        • Liu E.
        • Tager A.M.
        • Yuan Q.
        • Lin A.Y.
        • Ahluwalia N.
        • et al.
        Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells.
        Circulation. 2006; 113: 2301-2312
        • Fousek K.
        • Horn L.A.
        • Palena C.
        Interleukin-8: A chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression.
        Pharmacol Ther. 2021; 219107692
        • Gimbrone Jr., M.A.
        • Garcia-Cardena G.
        Endothelial cell dysfunction and the pathobiology of atherosclerosis.
        Circ Res. 2016; 118: 620-636
        • Tabas I.
        • Lichtman A.H.
        Monocyte-macrophages and t cells in atherosclerosis.
        Immunity. 2017; 47: 621-634
        • Doyle B.
        • Caplice N.
        Plaque neovascularization and antiangiogenic therapy for atherosclerosis.
        J Am Coll Cardiol. 2007; 49: 2073-2080
        • Arnaout M.A.
        • Goodman S.L.
        • Xiong J.P.
        Structure and mechanics of integrin-based cell adhesion.
        Curr Opin Cell Biol. 2007; 19: 495-507
        • D’Atri L.P.
        • Etulain J.
        • Rivadeneyra L.
        • Lapponi M.J.
        • Centurion M.
        • Cheng K.
        • et al.
        Expression and functionality of toll-like receptor 3 in the megakaryocytic lineage.
        J Thromb Haemost. 2015; 13: 839-850
        • Etulain J.
        • Schattner M.
        Glycobiology of platelet-endothelial cell interactions.
        Glycobiology. 2014; 24: 1252-1259
        • Ishibashi M.
        • Sayers S.
        • D’Armiento J.M.
        • Tall A.R.
        • Welch C.L.
        TLR3 deficiency protects against collagen degradation and medial destruction in murine atherosclerotic plaques.
        Atherosclerosis. 2013; 229: 52-61
        • Seneviratne A.N.
        • Monaco C.
        Role of inflammatory cells and toll-like receptors in atherosclerosis.
        Curr Vasc Pharmacol. 2015; 13: 146-160
        • Tall A.R.
        • Yvan-Charvet L.
        Cholesterol, inflammation and innate immunity.
        Nat Rev Immunol. 2015; 15: 104-116
        • Higashimori M.
        • Tatro J.B.
        • Moore K.J.
        • Mendelsohn M.E.
        • Galper J.B.
        • Beasley D.
        Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice.
        Arterioscler Thromb Vasc Biol. 2011; 31: 50-57
        • Crea F.
        • Libby P.
        Acute coronary Ssyndromes: The way forward from mechanisms to precision treatment.
        Circulation. 2017; 136: 1155-1166
        • Quillard T.
        • Araujo H.A.
        • Franck G.
        • Shvartz E.
        • Sukhova G.
        • Libby P.
        TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion.
        Eur Heart J. 2015; 36: 1394-1404
        • Falck-Hansen M.
        • Kassiteridi C.
        • Monaco C.
        Toll-like receptors in atherosclerosis.
        Int J Mol Sci. 2013; 14: 14008-14023
        • Kalekar L.A.
        • Schmiel S.E.
        • Nandiwada S.L.
        • Lam W.Y.
        • Barsness L.O.
        • Zhang N.
        • et al.
        CD4(+) T cell anergy prevents autoimmunity and generates regulatory T cell precursors.
        Nat Immunol. 2016; 17: 304-314
        • Schenten D.
        • Nish S.A.
        • Yu S.
        • Yan X.
        • Lee H.K.
        • Brodsky I.
        • et al.
        Signaling through the adaptor molecule MyD88 in CD4+ T cells is required to overcome suppression by regulatory T cells.
        Immunity. 2014; 40: 78-90
        • Subramanian M.
        • Thorp E.
        • Hansson G.K.
        • Tabas I.
        Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs.
        J Clin Invest. 2013; 123: 179-188
        • Alexander S.P.
        • Kelly E.
        • Marrion N.V.
        • Peters J.A.
        • Faccenda E.
        • Harding S.D.
        • et al.
        The Concise Guide To Pharmacology 2017/18: Overview.
        Br J Pharmacol. 2017; 174: S1-S16
        • Martini E.
        • Kunderfranco P.
        • Peano C.
        • Carullo P.
        • Cremonesi M.
        • Schorn T.
        • et al.
        Single-cell sequencing of mouse heart immune infiltrate in pressure overload-driven heart failure reveals extent of immune activation.
        Circulation. 2019; 140: 2089-2107
        • Tang X.
        • Pan L.
        • Zhao S.
        • Dai F.
        • Chao M.
        • Jiang H.
        • et al.
        SNO-MLP (S-Nitrosylation of muscle LIM protein) facilitates myocardial hypertrophy through TLR3 (toll-like receptor 3)-mediated RIP3 (receptor-interacting protein kinase 3) and NLRP3 (NOD-like receptor pyrin domain containing 3) inflammasome activation.
        Circulation. 2020; 141: 984-1000
        • Tripathi D.
        • Biswas B.
        • Manhas A.
        • Singh A.
        • Goyal D.
        • Gaestel M.
        • et al.
        Proinflammatory effect of endothelial microparticles is mitochondria mediated and modulated through MAPKAPK2 (MAPK-activated protein kinase 2) leading to attenuation of cardiac hypertrophy.
        Arterioscler Thromb Vasc Biol. 2019; 39: 1100-1112
        • Zhang Y.
        • Huang Z.
        • Li H.
        Insights into innate immune signalling in controlling cardiac remodelling.
        Cardiovasc Res. 2017; 113: 1538-1550
        • Rizza S.
        • Filomeni G.
        Chronicles of a reductase: Biochemistry, genetics and physio-pathological role of GSNOR.
        Free Radic Biol Med. 2017; 110: 19-30
        • Hayashi H.
        • Hess D.T.
        • Zhang R.
        • Sugi K.
        • Gao H.
        • Tan B.L.
        • et al.
        S-Nitrosylation of beta-arrestins biases receptor signaling and confers ligand independence.
        Mol Cell. 2018; 70: 473-487.e6
        • Wang W.
        • Wang D.
        • Kong C.
        • Li S.
        • Xie L.
        • Lin Z.
        • et al.
        eNOS S-nitrosylation mediated OxLDL-induced endothelial dysfunction via increasing the interaction of eNOS with betacatenin.
        Biochim Biophys Acta Mol Basis Dis. 2019; 1865: 1793-1801
        • Zamorano P.
        • Marin N.
        • Cordova F.
        • Aguilar A.
        • Meininger C.
        • Boric M.P.
        • et al.
        S-nitrosylation of VASP at cysteine 64 mediates the inflammation-stimulated increase in microvascular permeability.
        Am J Physiol Heart Circ Physiol. 2017; 313: H66-H71
        • Buyandelger B.
        • Ng K.E.
        • Miocic S.
        • Piotrowska I.
        • Gunkel S.
        • Ku C.H.
        • et al.
        MLP (muscle LIM protein) as a stress sensor in the heart.
        Pflugers Arch. 2011; 462: 135-142
        • Li X.
        • Lu W.J.
        • Li Y.
        • Wu F.
        • Bai R.
        • Ma S.
        • et al.
        MLP-deficient human pluripotent stem cell derived cardiomyocytes develop hypertrophic cardiomyopathy and heart failure phenotypes due to abnormal calcium handling.
        Cell Death Dis. 2019; 10: 610
        • Lange S.
        • Gehmlich K.
        • Lun A.S.
        • Blondelle J.
        • Hooper C.
        • Dalton N.D.
        • et al.
        MLP and CARP are linked to chronic PKCalpha signalling in dilated cardiomyopathy.
        Nat Commun. 2016; 7: 12120
        • Vafiadaki E.
        • Arvanitis D.A.
        • Sanoudou D.
        Muscle LIM protein: Master regulator of cardiac and skeletal muscle functions.
        Gene. 2015; 566: 1-7
        • Kaiser W.J.
        • Sridharan H.
        • Huang C.
        • Mandal P.
        • Upton J.W.
        • Gough P.J.
        • et al.
        Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL.
        J Biol Chem. 2013; 288: 31268-31279
        • Zhang T.
        • Zhang Y.
        • Cui M.
        • Jin L.
        • Wang Y.
        • Lv F.
        • et al.
        CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis.
        Nat Med. 2016; 22: 175-182
        • Qin D.
        • Wang X.
        • Li Y.
        • Yang L.
        • Wang R.
        • Peng J.
        • et al.
        MicroRNA-223-5p and -3p cooperatively suppress necroptosis in ischemic/reperfused hearts.
        J Biol Chem. 2016; 291: 20247-20259
        • Zhang X.
        • Fan C.
        • Zhang H.
        • Zhao Q.
        • Liu Y.
        • Xu C.
        • et al.
        MLKL and FADD are critical for suppressing progressive lymphoproliferative disease and activating the NLRP3 inflammasome.
        Cell Rep. 2016; 16: 3247-3259
        • Singh M.V.
        • Cicha M.Z.
        • Meyerholz D.K.
        • Chapleau M.W.
        • Abboud F.M.
        Dual ctivation of TRIF and MyD88 adaptor proteins by angiotensin II evokes opposing effects on pressure, cardiac hypertrophy, and inflammatory gene expression.
        Hypertension. 2015; 66: 647-656
        • Singh M.V.
        • Cicha M.Z.
        • Nunez S.
        • Meyerholz D.K.
        • Chapleau M.W.
        • Abboud F.M.
        Angiotensin II-induced hypertension and cardiac hypertrophy are differentially mediated by TLR3- and TLR4-dependent pathways.
        Am J Physiol Heart Circ Physiol. 2019; 316: H1027-H1038
        • Dange R.B.
        • Agarwal D.
        • Masson G.S.
        • Vila J.
        • Wilson B.
        • Nair A.
        • et al.
        Central blockade of TLR4 improves cardiac function and attenuates myocardial inflammation in angiotensin II-induced hypertension.
        Cardiovasc Res. 2014; 103: 17-27
        • Matsuda S.
        • Umemoto S.
        • Yoshimura K.
        • Itoh S.
        • Murata T.
        • Fukai T.
        • et al.
        Angiotensin activates MCP-1 and induces cardiac hypertrophy and dysfunction via toll-like receptor 4.
        J Atheroscler Thromb. 2015; 22: 833-844
        • Gao T.
        • Zhang S.P.
        • Wang J.F.
        • Liu L.
        • Wang Y.
        • Cao Z.Y.
        • et al.
        TLR3 contributes to persistent autophagy and heart failure in mice after myocardial infarction.
        J Cell Mol Med. 2018; 22: 395-408
        • Mann D.L.
        Innate immunity and the failing heart: the cytokine hypothesis revisited.
        Circ Res. 2015; 116: 1254-1268
        • Yu L.
        • Feng Z.
        The role of toll-like receptor signaling in the progression of heart failure.
        Mediators Inflamm. 2018; 9874109https://doi.org/10.1155/2018/9874109
        • Tang Y.
        • Xu Z.
        • Chen X.
        • Wang N.
        • Deng X.
        • Peng L.
        • et al.
        Effects of enalapril on TLR2/NF-kappaB signaling pathway and inflammatory factors in rabbits with chronic heart failure.
        Evid Based Complement Alternat Med. 2021; 9594607https://doi.org/10.1155/2021/9594607
        • Gao W.
        • Xiong Y.
        • Li Q.
        • Yang H.
        Inhibition of toll-like receptor signaling as a promising therapy for inflammatory diseases: A journey from molecular to nano therapeutics.
        Front Physiol. 2017; 8: 508
        • Ehrentraut H.
        • Weber C.
        • Ehrentraut S.
        • Schwederski M.
        • Boehm O.
        • Knuefermann P.
        • et al.
        The toll-like receptor 4-antagonist eritoran reduces murine cardiac hypertrophy.
        Eur J Heart Fail. 2011; 13: 602-610
        • Dhondup Y.
        • Ueland T.
        • Dahl C.P.
        • Askevold E.T.
        • Sandanger O.
        • Fiane A.
        • et al.
        Low circulating levels of mitochondrial and high levels of nuclear DNA predict mortality in chronic heart failure.
        J Card Fail. 2016; 22: 823-828
        • Virani S.S.
        • Alonso A.
        • Benjamin E.J.
        • Bittencour M.S.
        • Callaway C.W.
        • Carson A.P.
        • et al.
        Heart Disease and Stroke Statistics-2020 Update: A report from the American Heart Association.
        Circulation. 2020; 141: e139-e596
        • Yellon D.M.
        • Hausenloy D.J.
        Myocardial reperfusion injury.
        N Engl J Med. 2007; 357: 1121-1135
        • Heusch G.
        Treatment of myocardial ischemia/reperfusion injury by ischemic and pharmacological postconditioning.
        Compr Physiol. 2015; 5: 1123-1145
        • Neri M.
        • Riezzo I.
        • Pascale N.
        • Pomara C.
        • Turillazzi E.
        Ischemia/Reperfusion injury following acute myocardial infarction: A critical issue for clinicians and forensic pathologists.
        Mediators Inflamm. 2017; 7018393https://doi.org/10.1155/2017/7018393
        • Frangogiannis N.G.
        The inflammatory response in myocardial injury, repair, and remodelling.
        Nat Rev Cardiol. 2014; 11: 255-265
        • Lu C.
        • Ren D.
        • Wang X.
        • Ha T.
        • Liu L.
        • Lee E.J.
        • et al.
        Toll-like receptor 3 plays a role in myocardial infarction and ischemia/reperfusion injury.
        Biochim Biophys Acta. 2014; 1842: 22-31
        • Silvis M.J.M.
        • Kaffka Genaamd Dengler S.E.
        • Odille C.A.
        • Mishra M.
        • van der Kaaij N.P.
        • Doevendans P.A.
        • et al.
        Damage-associated molecular patterns in myocardial infarction and heart transplantation: The road to translational success.
        Front Immunol. 2020; 11599511https://doi.org/10.3389/fimmu.2020.599511
        • Liu S.
        • Cai X.
        • Wu J.
        • Cong Q.
        • Chen X.
        • Li T.
        • et al.
        Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation.
        Science. 2015; 347aaa2630
        • King K.R.
        • Aguirre A.D.
        • Ye Y.X.
        • Sun Y.
        • Roh J.D.
        • Ng Jr., R.P.
        • et al.
        IRF3 and type I interferons fuel a fatal response to myocardial infarction.
        Nat Med. 2017; 23: 1481-1487
        • Lee J.
        • Sayed N.
        • Hunter A.
        • Au K.F.
        • Wong W.H.
        • Mocarski E.S.
        • et al.
        Activation of innate immunity is required for efficient nuclear reprogramming.
        Cell. 2012; 151: 547-558
        • Grote K.
        • Schuett H.
        • Salguero G.
        • Grothusen C.
        • Jagielska J.
        • Drexler H.
        • et al.
        Toll-like receptor 2/6 stimulation promotes angiogenesis via GM-CSF as a potential strategy for immune defense and tissue regeneration.
        Blood. 2010; 115: 2543-2552
        • Lu M.
        • Tan F.
        • Zhang J.
        • Luan A.
        • Mei M.
        • Xu C.
        • et al.
        Astragaloside IV attenuates injury caused by myocardial ischemia/reperfusion in rats via regulation of toll-like receptor 4/nuclear factor-kappaB signaling pathway.
        Phytother Res. 2015; 29: 599-606
        • Wang Y.
        • Wang L.
        • Li J.H.
        • Zhao H.W.
        • Zhang F.Z.
        Morphine alleviates myocardial ischemia/reperfusion injury in rats by inhibiting TLR4/NF-kappaB signaling pathway.
        Eur Rev Med Pharmacol Sci. 2019; 23: 8616-8624
        • Xu W.
        • Zhang K.
        • Zhang Y.
        • Ma S.
        • Jin D.
        Downregulation of DEC1 by RNA interference attenuates ischemia/reperfusion-induced myocardial inflammation by inhibiting the TLR4/NF-kappaB signaling pathway.
        Exp Ther Med. 2020; 20: 343-350
        • Zhang J.J.
        • Peng K.
        • Zhang J.
        • Meng X.W.
        • Ji F.H.
        Dexmedetomidine preconditioning may attenuate myocardial ischemia/reperfusion injury by down-regulating the HMGB1-TLR4-MyD88-NF-small ka, CyrillicB signaling pathway.
        PLoS One. 2017; 12e0172006
        • Duerr G.D.
        • Wu S.
        • Schneider M.L.
        • Marggraf V.
        • Weisheit C.K.
        • Velten M.
        • et al.
        CpG postconditioning after reperfused myocardial infarction is associated with modulated inflammation, less apoptosis, and better left ventricular function.
        Am J Physiol Heart Circ Physiol. 2020; 319: H995-H1007
        • Arslan F.
        • Smeets M.B.
        • O’Neill L.A.
        • Keogh B.
        • McGuirk P.
        • Timmers L.
        • et al.
        Myocardial ischemia/reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody.
        Circulation. 2010; 121: 80-90
        • Kuznik A.
        • Bencina M.
        • Svajger U.
        • Jeras M.
        • Rozman B.
        • Jerala R.
        Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines.
        J Immunol. 2011; 186: 4794-4804
        • Gomez-Guzman M.
        • Jimenez R.
        • Romero M.
        • Sanchez M.
        • Zarzuelo M.J.
        • Gomez-Morales M.
        • et al.
        Chronic hydroxychloroquine improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematosus.
        Hypertension. 2014; 64: 330-337
        • Long L.
        • Yang X.
        • Southwood M.
        • Lu J.
        • Marciniak S.J.
        • Dunmore B.J.
        • et al.
        Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation.
        Circ Res. 2013; 112: 1159-1170
        • Holfeld J.
        • Tepekoylu C.
        • Kozaryn R.
        • Urbschat A.
        • Zacharowski K.
        • Grimm M.
        • et al.
        Shockwave therapy differentially stimulates endothelial cells: implications on the control of inflammation via toll-Like receptor 3.
        Inflammation. 2014; 37: 65-70
        • Mittermayr R.
        • Antonic V.
        • Hartinger J.
        • Kaufmann H.
        • Redl H.
        • Teot L.
        • et al.
        Extracorporeal shock wave therapy (ESWT) for wound healing: technology, mechanisms, and clinical efficacy.
        Wound Repair Regen. 2012; 20: 456-465