title: Pattern of cardiotoxin-induced muscle remodeling in distinct TLR-4 deficient mouse strains.
abstract: 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 Ly6Cnegmacrophages in Tlr4-/-mice at 3 DPI indicates that TLR-4 may influence the differentiation into Ly6Cnegor 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.
authors.affiliation: Department of Immunobiology, Institute of Biology, Fluminense Federal University, Niterói, Rio de Janeiro, 24 020 141, Brazil.|Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil.
authors.forename: Eustáquio Luiz
authors.initials: EL
authors.lastname: Paiva-Oliveira
authors.affiliation: Department of Immunobiology, Institute of Biology, Fluminense Federal University, Niterói, Rio de Janeiro, 24 020 141, Brazil.|Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil.
authors.forename: Rafael Ferreira
authors.initials: RF
authors.lastname: da Silva
authors.affiliation: Institute of Microbiology, Rio de Janeiro Federal University, Rio de Janeiro, Brazil.
authors.forename: Maria
authors.initials: M
authors.lastname: Bellio
authors.affiliation: Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil.
authors.forename: Thereza
authors.initials: T
authors.lastname: Quirico-Santos
authors.affiliation: Department of Immunobiology, Institute of Biology, Fluminense Federal University, Niterói, Rio de Janeiro, 24 020 141, Brazil. jlagrota@id.uff.br.
authors.forename: Jussara
authors.identifier: http://orcid.org/0000-0002-6573-561X
authors.initials: J
authors.lastname: Lagrota-Candido
mesh_terms: D000818:Animals; D054715:Cardiotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000378:metabolism
chemical_list: D054715:Cardiotoxins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: Cardiotoxin; Skeletal muscle; tissue repair; Toll-Like 4 receptor