Neutrophil-derived JAML inhibits repair of intestinal epithelial injury during acute inflammation

Abstract

Neutrophil transepithelial migration (TEM) during acute inflammation is associated with mucosal injury. Using models of acute mucosal injury in-vitro and in-vivo, we describe a new mechanism by which neutrophils infiltrating the intestinal mucosa disrupt epithelial homeostasis. We report that junctional adhesion molecule-like protein (JAML) is cleaved from neutrophil surface by zinc-metalloproteases during TEM. Neutrophil-derived soluble JAML bound to the epithelial tight junction protein coxsackie-adenovirus receptor (CAR) resulting in compromised barrier and inhibition of wound repair, through decreased epithelial proliferation. The deleterious effects of JAML on barrier and wound repair were reversed with an anti-JAML mAb that inhibits JAML-CAR binding. Thus, JAML released from transmigrating neutrophils across inflamed epithelia can promote recruitment of leukocytes and aid in clearance of invading microorganisms. However, sustained release of JAML under pathologic conditions associated with persistence of large numbers of infiltrated neutrophil would compromise intestinal barrier and inhibit mucosal healing. Targeting JAML-CAR interactions may thus improve mucosal healing responses under conditions of dysregulated neutrophil recruitment.

Neutrophil-Epithelial Interactions

“…81 Subsequent studies have revealed that JAML is shed from activated neutrophils during transepithelial migration, and shed ectodomains retain binding to epithelial CAR, resulting in signaling events that inhibit barrier recovery and wound healing. 82 These results appear at odds with other reports of JAML-CAR interactions facilitating T-cellemediated wound healing in the skin of mice. 83 However, in those studies, prorestitutive signals were derived downstream of from T-cell expressed JAML, whereas the inhibitory signals during transepithelial migration of neutrophils were derived downstream of epithelial expressed CAR.…”

Interleukin-17A Aggravates Middle Ear Injury Induced by Streptococcus pneumoniae through the p38 Mitogen-Activated Protein Kinase Signaling Pathway

“…Meanwhile, hosts might suffer from damage caused by invading microbes and the immune response (13). For example, neutrophil transepithelial migration during inflammation increases epithelial permeability and tissue damage by altering the barrier function and homeostasis of the epithelium (31). Therefore, it is not surprising that the migration of abundant neutrophils across the epithelium facilitates host-induced tissue damage, which includes organ dysfunction and inflammation-related diseases and even leads to death (17,32,33).…”

Epithelial adhesion molecules and the regulation of intestinal homeostasis during neutrophil transepithelial migration

“…Instead, PMN shed JAML during TEM and the binding of soluble JAML to CAR resulted in faulty epithelial resealing and significantly impaired mucosal wound healing. 74 These findings defined CAR as a key regulator of intestinal homeostasis and identified a novel PMN infiltration mechanism that may affect both epithelial barrier and wound healing.…”

“…74,93,94 Similar to JAM-A, CAR can engage in homophilic interactions 95 ; however, it also binds JAML, a JAM-like protein expressed exclusively on PMNs, monocytes, and gd T-cells, 74,96 with high affinity. While these observations marked the CAR-JAML ligand pair as an attractive candidate for PMN trafficking regulation, a recent study found that inhibiting these interactions only had a minor effect on PMN TEM.…”

“…The inability to significantly impact PMN TEM by inhibition of these interactions was attributed to JAML shedding during PMN TEM. 74 The PMN TEM-regulating roles of other important epithelial TJ constituents, including claudins and tricellulin, are also unclear. Interestingly, PMN migration across endothelial monolayers has been shown to preferentially occur at tricellular junctions.…”