Inflammatory macrophages switch to CCL17-expressing phenotype and promote peritoneal fibrosis
Journal
Journal of Pathology
Journal Volume
250
Journal Issue
1
Pages
55-66
Date Issued
2020
Author(s)
Hsu, Hao
Lin, Chi-Chun
Liu, Shin-Yun
Wu, Ching-Fang
Tsai, Pei-Zhen
Liao, Chia-Te
Abstract
Peritoneal fibrosis remains a problem in kidney failure patients treated with peritoneal dialysis. Severe peritoneal fibrosis with encapsulation or encapsulating peritoneal sclerosis is devastating and life-threatening. Although submesothelial fibroblasts as the major precursor of scar-producing myofibroblasts in animal models and M2 macrophage (M?)-derived chemokines in peritoneal effluents of patients before diagnosis of encapsulating peritoneal sclerosis have been identified, attenuation of peritoneal fibrosis is an unmet medical need partly because the mechanism for cross talk between M?s and fibroblasts remains unclear. We use a sodium hypochlorite-induced mouse model akin to clinical encapsulated peritoneal sclerosis to study how the peritoneal M?s activate fibroblasts and fibrosis. Sodium hypochlorite induces the disappearance of CD11bhighF4/80high resident M?s but accumulation of CD11bintF4/80int inflammatory M?s (InfM?s) through recruiting blood monocytes and activating local cell proliferation. InfM?s switch to express chemokine (C-C motif) ligand 17 (CCL17), CCL22, and arginase-1 from day 2 after hypochlorite injury. More than 75% of InfM?s undergo genetic recombination by Csf1r-driven Cre recombinase, providing the possibility to reduce myofibroblasts and fibrosis by diphtheria toxin-induced M? ablation from day 2 after injury. Furthermore, administration of antibody against CCL17 can reduce M?s, myofibroblasts, fibrosis, and improve peritoneal function after injury. Mechanistically, CCL17 stimulates migration and collagen production of submesothelial fibroblasts in culture. By breeding mice that are induced to express red fluorescent protein in M?s and green fluorescence protein (GFP) in Col1a1-expressing cells, we confirmed that M?s do not produce collagen in peritoneum before and after injury. However, small numbers of fibrocytes are found in fibrotic peritoneum of chimeric mice with bone marrow from Col1a1-GFP reporter mice, but they do not contribute to myofibroblasts. These data demonstrate that InfM?s switch to pro-fibrotic phenotype and activate peritoneal fibroblasts through CCL17 after injury. CCL17 blockade in patients with peritoneal fibrosis may provide a novel therapy. ? 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. ? 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
SDGs
Other Subjects
arginase 1; CD11b antigen; collagen type 1; cre recombinase; diphtheria toxin; green fluorescent protein; hypochlorite sodium; macrophage derived chemokine; macrophage inflammatory protein 1; macrophage inflammatory protein 2; red fluorescent protein; tamoxifen; thymus and activation regulated chemokine; transforming growth factor beta1; tumor necrosis factor; autacoid; Ccl17 protein, mouse; collagen type 1; collagen type I, alpha 1 chain; enhanced green fluorescent protein; green fluorescent protein; thymus and activation regulated chemokine; adult; animal cell; animal experiment; animal model; animal tissue; Article; cell activation; cell count; cell proliferation; controlled study; cross circulation; fibroblast; genetic recombination; human; inflammatory cell; macrophage; monocyte; mouse; myofibroblast; nonhuman; peripheral blood mononuclear cell; peritoneal fibrosis; phenotype; priority journal; animal; C57BL mouse; disease model; genetics; macrophage activation; metabolism; paracrine signaling; pathology; peritoneal fibrosis; peritoneum; peritoneum macrophage; phenotype; promoter region; signal transduction; transgenic mouse; Animals; Cell Proliferation; Chemokine CCL17; Collagen Type I; Disease Models, Animal; Fibroblasts; Green Fluorescent Proteins; Inflammation Mediators; Macrophage Activation; Macrophages, Peritoneal; Mice, Inbred C57BL; Mice, Transgenic; Paracrine Communication; Peritoneal Fibrosis; Peritoneum; Phenotype; Promoter Regions, Genetic; Signal Transduction; Sodium Hypochlorite
Publisher
John Wiley and Sons Ltd
Type
journal article