title: Reverse signaling through the costimulatory ligand CD137L in epithelial cells is essential for natural killer cell-mediated acute tissue inflammation.
abstract: Renal ischemia-reperfusion injury (IRI) after kidney transplantation is a major cause of delayed graft function. Even though IRI is recognized as a highly coordinated and specific process, the pathways and mechanisms through which the innate response is activated are poorly understood. In this study, we used a mouse model of acute kidney IRI to examine whether the interactions of costimulatory receptor CD137 and its ligand (CD137L) are involved in the early phase of acute kidney inflammation caused by IRI. We report here that the specific expressions of CD137 on natural killer cells and of CD137L on tubular epithelial cells (TECs) are required for acute kidney IRI. Reverse signaling through CD137L in TECs results in their production of the chemokine (C-X-C motif) receptor 2 ligands CXCL1 and CXCL2 and the subsequent induction of neutrophil recruitment, resulting in a cascade of proinflammatory events during kidney IRI. Our findings identify an innate pathogenic pathway for renal IRI involving the natural killer cell-TEC-neutrophil axis, whereby CD137-CD137L interactions provide the causal contribution of epithelial cell dysregulation to renal IRI. The CD137L reverse signaling pathway in epithelial cells therefore may represent a good target for blocking the initial stage of inflammatory diseases, including renal IRI.
authors.affiliation: School of Biological Sciences, Department of Internal Medicine, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Hye J
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jong S
authors.initials: JS
authors.lastname: Lee
authors.forename: Jung D
authors.initials: JD
authors.lastname: Kim
authors.forename: Hee J
authors.initials: HJ
authors.lastname: Cha
authors.forename: Ahra
authors.initials: A
authors.lastname: Kim
authors.forename: Sun K
authors.initials: SK
authors.lastname: Lee
authors.forename: Sang C
authors.initials: SC
authors.lastname: Lee
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mittler
authors.forename: Hong R
authors.initials: HR
authors.lastname: Cho
authors.forename: Byungsuk
authors.initials: B
authors.lastname: Kwon
mesh_terms: D053330:4-1BB Ligand / Q000172:deficiency / Q000276:immunology*; D019264:Adoptive Transfer; D000818:Animals; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D002633:Chemotaxis; D004847:Epithelial Cells / Q000276:immunology* / Q000637:transplantation; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000473:pathology*; D007684:Kidney Tubules / Q000276:immunology* / Q000473:pathology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology; D011961:Receptors, Fc / Q000276:immunology; D015427:Reperfusion Injury / Q000150:complications / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D011961:Receptors, Fc; C505975:Tnfsf9 protein, mouse