Recruitment of large peritoneal macrophages to capsular fibrosis developed on the liver surface

Abstract

Upon injury to Glisson's capsule, mesothelial cells covering the liver surface differentiate into myofibroblasts and participate in capsular fibrosis. In the fibrotic area, infiltrating macrophages are present, but their origin and role in capsular fibrosis remain elusive. In the present study, we examined whether macrophages in the peritoneal cavity migrate to the liver and participate in capsular fibrosis. Capsular fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate. Chlorhexidine gluconate treatment induced disappearance of CD11b^High F4/80^High large peritoneal macrophages from the peritoneal cavity. Transplantation of TIMD4⁺ large peritoneal macrophages to the mouse peritoneal cavity resulted in their recruitment to the fibrotic area of the liver. Bone marrow-derived monocytes were also recruited to the chlorhexidine gluconate-induced fibrotic area upon their transplantation to the peritoneal cavity. However, bone marrow-derived macrophages, Kupffer cells, peritoneal B cells, and small peritoneal macrophages prepared from chlorhexidine gluconate-treated mice did not exhibit such potential. In the hepatic fibrotic area, peritoneal macrophages lost expression of unique markers (Gata6, Timd4) and increased expression of genes involved in inflammation (Il1b, Il6, Tnf) and extracellular matrix remodeling (Mmp13, Timp1). Depletion of peritoneal macrophages by clodronate liposomes reduced capsular fibrosis. Our data indicate that large peritoneal macrophages are recruited to the injured liver surface and promote capsular fibrosis by inducing inflammation and extracellular matrix remodeling. Modulating the function of peritoneal macrophages might be a new approach for suppressing capsular fibrosis.

Keywords: Glisson's capsule; large peritoneal macrophages; liver fibrosis; mesothelial cells; peritoneal B cells.