Intestinal epithelial BLT1 promotes mucosal repair

Abstract

Acute and chronic intestinal inflammation is associated with epithelial damage, resulting in mucosal wounds in the forms of erosions and ulcers in the intestinal tract. Intestinal epithelial cells (IECs) and immune cells in the wound milieu secrete cytokines and lipid mediators to influence repair. Leukotriene B4 (LTB4), a lipid chemokine, binds to its receptor BLT1 and promotes migration of immune cells to sites of active inflammation, however a role for intestinal epithelial BLT1 during mucosal wound repair is not known. Here we report that BLT1 is expressed in IECs both in vitro and in vivo, where it functions as a receptor not only for LTB4 but also for another ligand Resolvin E1. Intestinal epithelial BLT1 expression is increased when epithelial cells are exposed to an inflammatory microenvironment. Using human and murine primary colonic epithelial cells, we reveal that LTB4-BLT1 pathway promotes epithelial migration and proliferation leading to accelerated epithelial wound repair. Furthermore, in vivo intestinal wound repair experiments in BLT1-deficient mice and bone marrow chimeras demonstrate an important contribution of epithelial BLT1 during colonic mucosal wound repair. Taken together, our findings show a novel pro-repair in IEC mechanism mediated by BLT1 signaling.

The leukotriene B4 receptors BLT1 and BLT2 as potential therapeutic targets

“…These findings suggest that BLT2 agonists could be used to treat intestinal ulcers and inflammatory bowel diseases. In addition to BLT2, the expression and protective roles of BLT1 in mucosal cells were reported 106 …”

“…In addition to BLT2, the expression and protective roles of BLT1 in mucosal cells were reported. 106…”

Emerging roles of host and microbial bioactive lipids in inflammatory bowel diseases

“…PUFA derivates manipulate epithelial barrier functions. Neutrophil‐derived leukotriene B 4 induces intestinal epithelial cell proliferation and migration by binding to BLT1, which is essential for mucosal wound healing [99]. Under homeostatic condition, PGE 2 is constitutively synthesized by COX1 at low level and enhances barrier functions of epithelial cells in the intestine [82].…”

Fatty acids and lipid mediators in inflammatory bowel disease: from mechanism to treatment

“…RvE1 suppresses pro-inflammatory cytokine TNF-α production, reducing leukocyte-mediated tissue damage and gene expression ( 119 ), ultimately improving histological scores in colitis mice and preventing colitis onset ( 118 , 119 ). BLT1 can serve as a receptor for RvE1, accelerating the intestinal epithelial barrier repair ( 199 ). RvD1, sourced from DHA, confers protection against IBD by strengthening tight junctions, maintaining intestinal homeostasis, and attenuating inflammation ( 120 ).…”