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RESEARCH PRODUCT

Toll-like receptor 5 deficiency exacerbates cardiac injury and inflammation induced by myocardial ischaemia-reperfusion in the mouse

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Myocardial ischaemia-reperfusion (MIR) triggers a sterile inflammatory response important for myocardial healing, but which may also contribute to adverse ventricular remodelling. Such inflammation is initiated by molecular danger signals released by damaged myocardium, which induce innate immune responses by activating toll-like receptors (TLRs). Detrimental roles have been recently reported for TLR2, TLR3 and TLR4. The role of other TLRs is unknown. We therefore evaluated the role of TLR5, expressed at high level in the heart, in the development of myocardial damage and inflammation acutely triggered by MIR. TLR5−/− and wild-type (WT) mice were exposed to MIR (30 min ischaemia, 2 h reperfusion). We measured infarct size, markers of cardiac oxidative stress, myocardial phosphorylation state of mitogen-activated protein (MAP) kinases and AKT, expression levels of chemokines and cytokines in the heart and plasma, as well as cardiac function by echography and conductance volumetry. TLR5-deficient mice had normal cardiac morphology and function under physiological conditions. After MIR, the absence of TLR5 promoted an increase in infarct size and myocardial oxidative stress. Lack of TLR5 fostered p38 phosphorylation, reduced AKT phosphorylation and markedly increased the expression of inflammatory cytokines, whereas it precipitated acute LV (left ventricle) dysfunction. Therefore, contrary to the detrimental roles of TLR2, TLR3 and TLR4 in the infarcted heart, TLR5 is important to limit myocardial damage, inflammation and functional compromise after MIR. Abbreviations: AAR, area at risk; CCL2, chemokine (C-C motif) ligand 2; CXCL2, chemokine (C-X-C motif) ligand 2; DAMP, damage-associated molecular pattern; Ees, end-systolic elastance; EF, ejection fraction; ERK, extracellular signal-regulated kinase; ESPVR, end-systolic pressure-volume relationship; FS, fractional shortening; HNE, hydroxynonenal; HRP, horseradish peroxidase; IL, interleukin; JNK, c-Jun N-terminal kinase; KC, keratinocyte chemoattractant; LV, left ventricle; LVEDD, left ventricle end-diastolic dimension; MAP kinase, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein 1; MDA, malondialdehyde; MI, myocardial infarction; MIR, myocardial ischaemia-reperfusion; MyD88, myeloid differentiation primary response gene 88; PBMC, peripheral blood mononuclear cell; Pes, end-systolic pressure; PMN, polymorphonuclear; PV, pressure-volume; TLR, toll-like receptor; Trif, toll-like receptor-associated activator of interferon; TTC, triphenyl tetrazolium chloride; V0, zero pressure intercept; Ved, end-diastolic volume; Ves, end-systolic volume; WT, wild-type