C-type lectin receptor LSECtin-mediated apoptotic cell clearance by macrophages directs intestinal repair in experimental colitis

Abstract

Epithelial barrier disruption is a major cause of inflammatory bowel disease (IBD); however, the cellular and molecular regulation of intestinal epithelial homeostasis remains largely undefined. Here, we show that the C-type lectin receptor LSECtin (Clec4g) on macrophages is required for protection against dextran sulfate sodium-induced colitis. Mechanistically, LSECtin promotes apoptotic cell clearance by macrophages and induces the production of antiinflammatory/tissue repair factors in an engulfment-dependent manner, which in turn stimulates epithelial cell proliferation. Deletion of LSECtin results in defective engulfment by colon macrophages, leading to aberrant proresolving factor production and impaired intestinal epithelium repair. Collectively, our findings suggest that LSECtin-dependent corpse clearance by macrophages can direct intestinal regeneration and maintenance of the mucosal barrier after injury.

Activation of mTORC1 by LSECtin in macrophages directs intestinal repair in inflammatory bowel disease

“…Our previous studies revealed that LSECtin, which is located in macrophages, facilitated macrophage phagocytosis of apoptotic cells to promote the proliferation of epithelial cells and ameliorate colitis 12 . To explore how LSECtin regulates macrophage-directed intestinal regeneration in experimental colitis, we sought to identify LSECtin-interacting proteins.…”

“…We isolated lamina propria mononuclear cells (LPMCs) from the colons of LSECtin wild-type (WT) and knock-out (KO) mice and detected the activation levels of mTORC1. Given that LSECtin is highly expressed in colonic macrophages 12 , we used LPMCs to represent colonic macrophages roughly. As expected, LSECtin was detected in the LSECtin-WT mice but not in the LSECtin-KO mice (Fig.…”

“…Similar to DC-SIGN and L-SIGN, LSECtin functions as an endocytic receptor and mediates the binding and internalization of relevant apoptotic cells and viruses 14 , 22 . Findings from our recent study revealed that LSECtin, which is located on intestinal macrophages, promotes macrophage phagocytosis of apoptotic cells, contributing to tissue homeostasis in colitis 12 . However, the molecular mechanisms by which LSECtin senses apoptotic cells and restores tissue homeostasis in macrophages have not been fully elucidated.…”

“…The signaling pathways and functional outcomes of downstream CLRs, which sense apoptotic cells, are not understood. LSECtin (encoded by Clec4g ), which belongs to the CLR superfamily, is a type II transmembrane protein that has been previously detected on liver-resident macrophages called Kupffer cells (KCs) and intestinal macrophages 12 , 19 , 20 . LSECtin acts as a coinhibitory molecule and limits T cell immunity to promote hepatitis B virus tolerance 20 , 21 .…”

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

“…Macrophage transcription factors Kruppel-like factors 2 (KLF2) and 4 (KLF4) are crucial controllers inducing gene expression necessary to silently eradicate apoptotic cells [138]. Recently, Yang et al reported that the C-type lectin receptor LSECtin (Clec4g) on colon macrophages is required for macrophage engulfment and clearance of apoptotic cells, contributing to intestinal repair in dextran sulphate sodium-induced colitis [146]. Interestingly, activated Treg cells secrete IL-13 to stimulate IL-10 production in macrophages via binding to the IL-13 receptor.…”