Pattern of cardiotoxin-induced muscle remodeling in distinct TLR-4 deficient mouse strains

Tissue damage triggers innate immune response mediated by Toll-like receptor 4 (TLR) that recognizes endogenous host danger molecules associated with cell death and tissue inflammation, although the precise role of TLR-4 signaling in muscle tissue repair is still uncertain. Previously, we observed that TLR-4 exerted a protective effect preventing excessive muscular damage induced by Bothrops jararacussu crude venom. This study aimed to evaluate the involvement of TLR-4 at early stages of muscular tissue remodeling in distinct mouse strains after injection of purified snake venom. Muscular injury was induced by injection of 25 µl (0.05 mg/ml) of cardiotoxin (CTX) from Naja mossambica in the gastrocnemius muscle of C3H/HeN (wild-type); C3H/HeJ mice that express a non-functional TLR-4 receptor, C57BL/6 and Tlr4 −/− (B6 background) mice. Comparing to control, Tlr4 −/− mice presented at early stages (3 DPI) of muscle injury mild inflammation with low MMP-9 activity, scarce macrophage infiltration and premature change to anti-inflammatory phenotype, low TNF-α mRNA levels and reduced myogenin expression, with low regeneration and tissue remodeling. The presence of more Ly6C neg macrophages in Tlr4 −/− mice at 3 DPI indicates that TLR-4 may influence the differentiation into Ly6C neg or likely affect proliferation of such cells in the muscle. The present study shows that TLR-4 deficiency and genetic background influence the outcome of muscular tissue repair in aseptic lesions and yet still maintaining some level of signaling in the TLR4-mutant mice.