Novel Junctional Adhesion Molecule‐Like (JAML) Regulates Neutrophil Transepithelial Migration During Intestinal Inflammation

Neutrophil (PMN) migration in the intestine is an essential component of host defense and wound repair. However, dysregulated PMN recruitment is a hallmark of inflammatory bowel disease (IBD). Disease flares in IBD are associated with robust PMN migrating across the intestinal mucosa resulting in crypt abscess formation and mucosal ulceration. Despite strong association of PMN infiltration into the gut with patient symptoms in IBD, the molecular basis of PMN transepithelial migration (TEpM) represents a significantly understudied area. It is now appreciated that PMN migration into intestinal mucosa requires multiple adhesive interactions between migrating PMN and intestinal epithelial cells (IECs), that represents a multi‐step process facilitated by complex interactions between PMN and IEC expressed proteins including members of the Junctional Adhesion Molecules (JAMs) family. We have reported that the novel JAM‐like protein termed JAML expressed on PMN, associates with the coxsackie and adenovirus receptor (CAR) expressed on epithelial cells. Binding of soluble JAML ectodomains to CAR has been shown to disrupt JAML‐CAR interactions and reduce PMN TEpM in‐vitro. To define the molecular mechanism of JAML regulation of PMN TEpM during intestinal inflammation in‐vivo, we generated JAML knockout mice ( JAML −/− ). PMN TEpM was evaluated using a small intestinal loop model, and PMN migration in response to the chemoattractant LTB 4 (1nM) quantified by flow cytometry. While WT and JAML −/− mice had similar numbers of circulating leukocytes, we observed reduced PMN TEpM in‐vivo in JAML −/− mice compared to WT animals. This decrease in PMN traffic into the lumen was associated with increased retention of PMN within the intestinal epithelium in JAML −/− mice. In addition, epithelial accumulation of PMN in JAML −/− mice paralleled an increase in intestinal permeability to a 4KDa FITC‐dextran as detected by fluorescence intensity in serum. Finally, we studied the role of JAML on susceptibility to DSS induced colitis. Loss of JAML markedly increased disease activity index, inflammation and mucosal ulceration compared to WT mice. Overall, these observations suggest that JAML is an important adhesion molecule that regulates PMN TEpM in the intestinal mucosa. JAML thus represents a new therapeutic target to dampen excessive PMN migration during intestinal inflammation as seen in IBD. Support or Funding Information CCFA CDA454814 and NIH 3R01 DK072564‐23S1 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .