Junctional adhesion molecule-A-deficient polymorphonuclear cells show reduced diapedesis in peritonitis and heart ischemia-reperfusion injury

Abstract

Junctional Adhesion Molecule-A (JAM-A) is a transmembrane adhesive protein expressed at endothelial junctions and in leukocytes. Here we report that JAM-A is required for the correct infiltration of polymorphonuclear leukocytes (PMN) into an inflamed peritoneum or in the heart upon ischemia-reperfusion injury. The defect was not observed in mice with an endotheliumrestricted deficiency of the protein but was still detectable in mice transplanted with bone marrow from JAM-A ؊/؊ donors. Microscopic examination of mesenteric and heart microvasculature of JAM-A ؊/؊ mice showed high numbers of PMN adherent on the endothelium or entrapped between endothelial cells and the basement membrane. In vitro, in the absence of JAM-A, PMN adhered more efficiently to endothelial cells and basement membrane proteins, and their polarized movement was strongly reduced. This paper describes a nonredundant role of JAM-A in controlling PMN diapedesis through the vessel wall.endothelial cell junctions ͉ leukocyte transmigration ͉ myocardial infarction ͉ polymorphonuclear leukocytes

Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1

“…4 Leukocyte JAM-A has also been shown to mediate directional leukocyte migration, a response that may facilitate leukocyte migration through EC junctions and beyond in certain inflammatory scenarios. 4,42 In conclusion, results presented here demonstrate the ability of the EC adhesion molecules ICAM-2, JAM-A, and PECAM-1 to mediate neutrophil transmigration in a stimulus-dependent manner in multiple mouse strains and provide direct evidence to show that this phenomenon can be governed by the target cell being activated. Furthermore, the findings show that ICAM-2, JAM-A, and PECAM-1 mediate distinct but sequential steps in the transmigration process to support emigration of neutrophils through venular walls in vivo.…”

“…The dual and triple functional blockade studies provided no evidence to suggest that ICAM-2, JAM-A, and PECAM-1 act in an additive manner, suggesting that they may act in sequence to mediate neutrophil emigration through venular walls. Although complete inhibition was not seen, it is thought that these data do represent a true inhibition rather than a delay in transmigration based on previous studies, 8,42 which observed dynamic changes in the number of transmigrated leukocytes over time and saw no evidence for numbers "catching up" in the absence of functional JAM-A. Our previous studies have shown that JAM-A and PECAM-1 act at distinct steps in the transmigration process, with JAM-A mediating neutrophil migration at the level of the endothelium and PECAM-1 supporting leukocyte transmigration at the level of the vascular BM.…”

The immune system and cardiac repair

“…Microscopic examination of the heart microvasculature showed large numbers of neutrophils adherent on the endothelium, or entrapped between endothelial cells and the basement membrane. These defects were associated with enhanced cardiomyocyte injury in JAM-A null infarcts, perhaps due to impaired blood flow caused by prolonged entrapment of neutrophils in the microcirculation [206].…”

“…Junctional adhesion molecules (JAMs) of tight junctions are regulated by phosphorylation [177] and play an essential role in Transendothelial migration [205]. Corada and co-workers suggested an important role for the Junctional Adhesion Molecule (JAM)-A in regulating neutrophil infiltration into the ischemic myocardium [206]. JAM-A −/− mice exhibited impaired neutrophil diapedesis following myocardial ischemia/ reperfusion.…”

Cellular recruitment in myocardial ischaemia/reperfusion injury

“…Among the latter ones playing an essential role, the absence of JAM-A resulted in impaired neutrophil diapedesis after myocardial ischaemia/reperfusion; moreover, JAM-A null infarcts showed an enhanced cardiomyocyte injury maybe because of an impaired blood flow due to the prolonged entrapment in the microcirculation [42].…”