title: Toll-like receptor 4 signaling regulates the acute local inflammatory response to injury and the fibrosis/neovascularization of sterile wounds.
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 IκBα degradation in J774.A1 macrophages. Results support a role for endogenous ligands of TLR4 in the regulation of inflammation and repair in sterile wounds.
authors.affiliation: Department of Surgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Samielle K
authors.initials: SK
authors.lastname: Brancato
authors.affiliation: Department of Surgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Alan A
authors.initials: AA
authors.lastname: Thomay
authors.affiliation: Department of Surgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Daley
authors.affiliation: Department of Surgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Crane
authors.affiliation: Department of Surgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Reichner
authors.affiliation: Department of Pathology, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel.
authors.forename: Edmond
authors.initials: E
authors.lastname: Sabo
authors.affiliation: Department of Surgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Albina
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000276:immunology; D054405:Chemokine CCL3 / Q000276:immunology; D018946:Chemokine CCL5 / Q000276:immunology; D054428:Chemokine CX3CL1 / Q000276:immunology; D018450:Disease Progression; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005355:Fibrosis / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000276:immunology*; D011142:Polyvinyl Alcohol; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014945:Wound Healing / Q000276:immunology*; D014947:Wounds and Injuries / Q000276:immunology*
chemical_list: C491768:Ccl2 protein, mouse; C496534:Ccl3 protein, mouse; C503460:Ccl5 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D018946:Chemokine CCL5; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C556062:IL10 protein, mouse; D015850:Interleukin-6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D016222:Fibroblast Growth Factor 2; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D011142:Polyvinyl Alcohol