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 acr… Show more
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Leukocyte transmigration into the central nervous system promotes multiple sclerosis pathogenesis, yet ambiguity remains regarding the mechanisms controlling the migration of distinct immune cell subsets. Using in vitro, ex vivo and postmortem human materials, we identified a significant upregulation of junctional adhesion molecule‐like expression at the blood–brain barrier, monocytes, and CD8 T cells of multiple sclerosis patients. We also detected junctional adhesion molecule‐like+ trans‐migratory cups when monocytes/CD8 T cells adhered to the blood–brain barrier, however, their migratory capacity was significantly compromised when junctional adhesion molecule‐like was blocked. These findings highlight a novel role for junctional adhesion molecule‐like in leukocyte transmigration and its potential as a promising therapeutic target.
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Leukocyte transmigration into the central nervous system promotes multiple sclerosis pathogenesis, yet ambiguity remains regarding the mechanisms controlling the migration of distinct immune cell subsets. Using in vitro, ex vivo and postmortem human materials, we identified a significant upregulation of junctional adhesion molecule‐like expression at the blood–brain barrier, monocytes, and CD8 T cells of multiple sclerosis patients. We also detected junctional adhesion molecule‐like+ trans‐migratory cups when monocytes/CD8 T cells adhered to the blood–brain barrier, however, their migratory capacity was significantly compromised when junctional adhesion molecule‐like was blocked. These findings highlight a novel role for junctional adhesion molecule‐like in leukocyte transmigration and its potential as a promising therapeutic target.
“…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.…”
Section: Discussionmentioning
confidence: 82%
“…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].…”
The coxsackie and adenovirus receptor (CAR), a putative cell-cell adhesion molecule, has attracted wide interest due to its importance in viral pathogenesis and in mediating adenoviral gene delivery. However, the distribution pattern and physiological function of CAR in the testis is still not clear. Here, we identified CAR in Sertoli cells and germ cells of rats. In vivo studies have shown that CAR resides at the blood-testis barrier as well as at the ectoplasmic specialization. The persistent expression of CAR in rat testes from neonatal period throughout adulthood implicates its role in spermatogenesis. Using primary Sertoli cell cultures, we observed a significant induction of CAR during the formation of Sertoli cell epithelium. Furthermore, CAR was seen to be concentrated at inter-Sertoli cell junctions, colocalizing with tight junction protein marker ZO-1 and adherens junction protein N-cadherin. CAR was also found to be associated with proteins of Src kinase family and its protein level declined after TNFα treatment in Sertoli cell cultures. Immunofluorescent staining of isolated germ cells has revealed the presence of CAR on spermatogonia, spermatocytes, round spermatids and elongate spermatids. Taken together, we propose that CAR functions as an adhesion molecule in maintaining the inter-Sertoli cell junctions at the basal compartment of the seminiferous epithelium. In addition, CAR may confer adhesion between Sertoli and germ cells at the Sertoli-germ cell interface. It is possible that the receptor utilized by viral pathogens to breakthrough the epithelial barrier was also employed by developing germ cells to migrate through the inter-Sertoli cell junctions.
The coxsackievirus and adenovirus receptor (CAR) is an essential multifunctional cellular protein that is only beginning to be understood. CAR serves as a receptor for many adenoviruses, human group B coxsackieviruses, swine vesicular disease virus, and possibly other viruses. While named for its function as a viral receptor, CAR is also involved in cell adhesion, immune cell activation, synaptic transmission, and signaling. Knockout mouse models were first to identify some of these biological functions; however, tissue‐specific model systems have shed light on the complexity of different CAR isoforms and their specific activities. Many of these functions are mediated by the large number of interacting proteins described so far, and several new putative interactions have recently been discovered. As antiviral and gene therapy strategies that target CAR continue to emerge, future work poised to understand the biological implications of manipulating CAR in vivo is critical.
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