Neutrophil Migration across Tight Junctions Is Mediated by Adhesive Interactions between Epithelial Coxsackie and Adenovirus Receptor and a Junctional Adhesion Molecule-like Protein on Neutrophils

Abstract

Neutrophil (polymorphonuclear leukocytes [PMN]) transepithelial migration during inflammatory episodes involves INTRODUCTIONPolymorphonuclear leukocytes (PMN) are the first line of host defense against infection by bacterial pathogens and are rapidly recruited to sites of bacterial invasion. Because the majority of pathogens are encountered at mucosal surfaces, PMN must migrate out of the circulation, through the interstitium and across the epithelium to engage offending microbes. Although migration of PMN across the epithelium in this response is a terminal event, it is vitally important since elimination of pathogens and disease pathophysiology are direct consequences of PMN transepithelial migration. Despite the importance of this terminal event in the acute inflammatory response, many of the details regarding the regulation of PMN migration across mucosal surfaces remain undefined. Studies on this have revealed that migration of PMN across epithelial barriers involves a concerted series of cell-cell interactions between the PMN and epithelial cells (Zen and Parkos, 2003;Liu et al., 2004b). There is solid evidence that initial PMN-epithelial binding requires leukocyte ␤ 2 integrins, especially CD11b/CD18 (Parkos, 1997) and that the rate of PMN migration between epithelial cells is dependent on downstream signaling events from binding interactions between epithelial CD47 and PMNexpressed signal regulatory protein ␣ . Recent studies have begun to shed light on the nature of additional receptor-ligand pairs that may regulate PMN transepithelial migration in an organ-specific manner that are distinct from processes regulating transendothelial migration.Although the leukocyte ␤ 2 integrin CD11b/CD18 is a key adhesive element that regulates PMN transepithelial migration, there is evidence that additional adhesion molecules expressed on both PMN and epithelia must participate in PMN transepithelial migration, especially at the level of epithelial intercellular junctions. Recently, certain members of a growing family of proteins termed junctional adhesion molecules (JAMs) that are intercellular junction-associated, type-I Ig superfamily proteins (IgSFs) have been shown to serve as ligands for PMN and monocytes as they migrate across endothelial (Martin-Padura et al., 1998;Del Maschio et al., 1999;Johnson-Leger et al., 2002;Ostermann et al., 2002) and epithelial monolayers (Zen et al., 2004 (Ebnet et al., 2000;Takekuni et al., 2003) or desmosomes (Zen et al., 2004). JAMs are differentially expressed on a variety of endothelia, epithelia, and leukocytes and, under specific conditions, have been shown to mediate homophilic or heterophilic binding interactions that are important in regulating epithelial/endothelial monolayer barrier function and leukocyte transmigration (Martin-Padura et al., 1998;Cunningham et al., 2000;Liu et al., 2000;Cohen et al., 2001;Johnson-Leger et al., 2002;Liang et al., 2002;Mandell et al., 2004). In addition to homophilic/heterophilic interactions among JAM proteins, two family members, JAM-A ...

JAML mediates monocyte and CD8 T cell migration across the brain endothelium

“…In addition, JAML expression on myeloid and CD8 T cells populations within the CNS is an important aspect that warrants further investigation as JAML is also a costimulatory molecule able to support cell activation and effector functions 13. The migration of neutrophils and monocytes across epithelium and EC lines was shown to be decreased when JAML is blocked 4, 14. Here, we show JAML expression by primary cultures of human BBB‐ECs and demonstrate that JAML blockade compromises the migration of monocytes and activated CD8 T cells.…”

“…Additional CAMs involved in this process are the junctional adhesion molecule (JAM) family (JAM‐A to C), which are type I transmembrane proteins differentially expressed at the junctions of ECs, epithelial cells, and on various leukocytes 3. A more recently identified member of this family, JAM like (JAML), is known to mediate the transmigration of neutrophils and monocytes by interacting with coxsackie‐adenovirus receptor (CAR) expressed by epithelia 4. JAML is also expressed by endothelium where it homodimerizes in cis, although homophilic trans interactions have been reported in areas of cell–cell contact 5.…”

Coxsackie and adenovirus receptor (CAR) is a product of Sertoli and germ cells in rat testes which is localized at the Sertoli–Sertoli and Sertoli–germ cell interface

“…Likewise, JAM-Like protein on neutrophils and CAR on T84 monolayer were found to promote the transepithelial migration of neutrophils by adhesive interactions [25]. Similar mechanisms could be utilized by developing preleptotene spermatocytes to migrate through the tight junctions between adjacent Sertoli cells, with CAR on the Sertoli cell surface interacting with JAM-C on the germ cell surface.…”

“…Sertoli cells and germ cells isolated with the above described protocol contained negligible contamination of other type of cells, which was verified by RT-PCR and immunoblotting analysis of cell-type specific protein markers [25]. For example, c-kit receptor was amplified by RT-PCR and probed in immunoblot to detect possible germ cell contamination.…”

“…For example, c-kit receptor was amplified by RT-PCR and probed in immunoblot to detect possible germ cell contamination. Likewise, testin, 3β-hydrosteroid dehydrogenase, and fibronectin were used to monitor the presence of contaminating Sertoli cells, Leydig cells and peritubular myoid cells, respectively [25].…”