| First Author | Chen YT | Year | 2020 |
| Journal | J Pathol | Volume | 250 |
| Issue | 1 | Pages | 55-66 |
| PubMed ID | 31579932 | Mgi Jnum | J:293530 |
| Mgi Id | MGI:6452894 | Doi | 10.1002/path.5350 |
| Citation | Chen YT, et al. (2020) Inflammatory macrophages switch to CCL17-expressing phenotype and promote peritoneal fibrosis. J Pathol 250(1):55-66 |
| abstractText | 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 (Mvarphi)-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 Mvarphis and fibroblasts remains unclear. We use a sodium hypochlorite-induced mouse model akin to clinical encapsulated peritoneal sclerosis to study how the peritoneal Mvarphis activate fibroblasts and fibrosis. Sodium hypochlorite induces the disappearance of CD11b(high) F4/80(high) resident Mvarphis but accumulation of CD11b(int) F4/80(int) inflammatory Mvarphis (InfMvarphis) through recruiting blood monocytes and activating local cell proliferation. InfMvarphis switch to express chemokine (C-C motif) ligand 17 (CCL17), CCL22, and arginase-1 from day 2 after hypochlorite injury. More than 75% of InfMvarphis undergo genetic recombination by Csf1r-driven Cre recombinase, providing the possibility to reduce myofibroblasts and fibrosis by diphtheria toxin-induced Mvarphi ablation from day 2 after injury. Furthermore, administration of antibody against CCL17 can reduce Mvarphis, 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 Mvarphis and green fluorescence protein (GFP) in Col1a1-expressing cells, we confirmed that Mvarphis 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 InfMvarphis 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. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
