Premium
Toll‐like receptor 4 signaling regulates the acute local inflammatory response to injury and the fibrosis/neovascularization of sterile wounds
Author(s) -
Brancato Samielle K.,
Thomay Alan A.,
Daley Jean M.,
Crane Meredith J.,
Reichner Jonathan S.,
Sabo Edmond,
Albina Jorge E.
Publication year - 2013
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/wrr.12061
Subject(s) - wound healing , ccl3 , fibrosis , chemokine , tlr4 , neovascularization , inflammation , angiogenesis , ccl2 , ccr2 , immunology , ccl5 , medicine , tumor necrosis factor alpha , chemokine receptor , cancer research , pathology , immune system , t cell , il 2 receptor
Abstract The role of Toll‐like receptor 4 ( TLR4 ) in the regulation of inflammation and fibrosis in sterile wounds was investigated in TLR4 signal‐deficient ( C3H / HeJ or TLR4 − / − ) and control mice using the subcutaneously implanted polyvinyl alcohol sponge wound model. Total and differential wound cell counts 1, 3, and 7 days after injury did not differ between C3H / HeJ and C3H / HeOuJ animals. Blood monocytes from both strains expressed CCR2 equally. Day one wounds in C3H / HeJ mice contained fewer Gr ‐1 high wound macrophages, CCL3 , and CCL5 , and more CCL17 than those in controls. The accumulation of CCL2 , CX3CL1 , tumor necrosis factor‐α, interleukin ( IL )‐6, IL ‐10, IL ‐12, and interferon‐γ in wound fluids was not TLR4 dependent. Wound macrophages from C3H / HeJ and C3H / HeOuJ mice expressed CCR4 and CCR5 , but not CCR1 or CCR3 . Wound macrophage recruitment was not altered in CCR5 − / − mice or in C3H / HeOuJ animals injected with neutralizing anti‐ CCL3 and anti‐ CCL5 antibodies. Neutralization of the CCR4 ligand CCL17 in C3H / HeJ mice did not alter wound macrophage populations. There was a twofold increase in collagen content and number of neovessels in 21‐day‐old wounds in C3H / HeJ vs. C3H / HeOuJ mice. There were no differences between strains in the number of myofibroblasts in the wounds 7 or 21 days postwounding. The increased fibrosis and angiogenesis in wounds from / HeJ mice correlated with higher concentrations of transforming growth factor‐β and fibroblast growth factor 2 in wound fluids from these animals. Wound fluids did not contain detectable lipopolysaccharide and did not induce I κ B α degradation in J774.A1 macrophages. Results support a role for endogenous ligands of TLR4 in the regulation of inflammation and repair in sterile wounds.