Lack of circulating toll-like receptor 2 promotes survival and prevents adverse remodeling after myocardial infarction

Purpose: Adverse cardiac remodeling after myocardial infarction is mediated by excessive inflammation. Toll-like receptors (TLR) are known for their crucial role in inflammatory responses after injury. In the present study, we investigated the role of TLR2 in adverse remodeling after myocardial infarction. Methods: C57Bl6 wild-type (WT), TLR2 -/- and chimeric (WT bone marrow transplanted in TLR2 -/- mice and vice versa) mice underwent permanent ligation of the left coronary artery. Cardiac function and geometry were assessed with 9.4T mouse-MRI at baseline, 7 and 28 days after infarction. Infarct size (IS) as a percentage of the left ventricle (LV) was determined by Evan's blue dye injection and TTC staining at 2 days (IS/LV). Fibroblast differentiation and activation was performed via immunohistochemical staining for αSMA and periostin. Inflammation in the remote and infarct area was assessed by expression of cytokines (multiplex). Results: TLR2 -/- mice showed improved survival compared to WT and were relatively protected against adverse cardiac remodeling during 28 days follow-up, despite similar infarct sizes (39±1.4% vs. 42±1.5%; p=0.256). Furthermore, systolic performance of both infarcted and remote myocardium was better in TLR2-/- mice compared to WT animals (ESV in ul: 112.4±6.2 vs. 207.4±15.7, p<0.001). Chimeric mice experiments demonstrated that bone marrow derived TLR2 expression mediated the expansive remodeling after infarction. Inflammatory cytokine levels (TNFα, IL-1α, GM-CSF and IL-10) and white blood cell count were significantly reduced in TLR2 -/- mice at resp. 3 days and 7 days after infarction. In addition, αSMA- and periostin-positive areas were significantly reduced in TLR2-/- animals at 3 and 7 days after infarction (periostin: 21.50±12.45% vs. 7.30±4.77%, p=0.02). Conclusions: Lack of TLR2 improves survival and cardiac function after myocardial infarction and is determined by leukocytic TLR2 deficiency via reduced inflammation. Current efforts are to clarify the reduced myofibroblast staining, suggesting a pivotal role for TLR2 in fibroblast and leucocyte transdifferentiation and activation. Future interventional studies are required to address the potential of TLR2 as a therapeutic target to prevent adverse remodeling after myocardial infarction.