A TLR4-MCP-1-macrophage IL-18 Cascade Plays A Major Role In Myocardial Injury And Cardiac Dysfunction After Permanent Ischemia

Abstract

Introduction: Myocardial ischemia induces an inflammatory response involving in up-regulated chemokine expression and macrophage (Mf) accumulation. Toll-like receptor 4 (TLR4) has been linked to post-ischemic myocardial injury, and it mediates myocardial expression of MCP-1, a key chemokine for Mfaccumulation, after ischemia. However, the role of Mfin post-ischemic myocardial injury and heart failure is not well understood. We hypothesize that TLR4 mediates myocardial injury through up-regulation of chemokine expression and macrophage accumulation. The purposes of this study were to determine: 1) the effect of TLR4 mutation on different chemokines expression, differential leukocytes accumulation, and myocardial injury in a mouse model of permanent, 2) whether neutralizing MCP-1 reduces Mfaccumulation and myocardial injury, 3) whether monocyte/Mfdepletion reduces myocardial injury and 4)to determine the role of IL-18 expressed by accumulated macrophage, in the myocardial injury. Methods: C3H/HeJ (TLR4 mutant, with dysfunctional TLR4) and C3H/HeN (TLR4-competent) mice were subjected to left coronary ligation. Results: In TLR4-competent mice, among chemokines only MCP-1 myocardial levels increased markedly at day 1, 3 and 7, and massive Mfaccumulation in the ischemic myocardium occurred at day 3 and 7. TLR4 mutation significantly reduced these changes, resulting in smaller infarct size and improved heart function. Neutralizing MCP-1 also reduced Mfaccumulation, infarct size and heart failure in TLR4-competent mice. Further, prior depletion of monocytes/Mfusing liposomal clodronate resulted in infarct size reduction and heart function improvement. Finally, suppression of Mfdecreased myocardial IL-18 levels in ischemic myocardium, and IL-18 knockout provided significant myocardial protection against injury and dysfunction but its effect was less robust than TLR4 mutation, MCP-1 neutralization or monocytes/Mfdepletion. Conclusions: A TLR4-MCP-1-macrophage-IL-18 cascade occupies a major in myocardial injury and cardiac dysfunction after permanent ischemia and could be a therapeutic target for protection against post-ischemic myocardial injury and heart failure.