Role of CXC Chemokine Receptor 3 Pathway in Renal Ischemic Injury

Abstract

I schemia-reperfusion (I/R) injury could lead to ischemic renal failure, which is one of the most common forms of acute renal failure of the native kidneys as well as of the renal allograft (1-5). Despite major advances in understanding the pathogenesis of I/R, no satisfactory therapy is available, and ischemic acute renal failure remains a major cause of morbidity and mortality (6). I/R injury begins with tissue hypoperfusion/hypoxia and leads to depletion of cellular ATP and cytoskeletal damage (7,8). Restoration of blood flow is accompanied by reperfusion injury, which is characterized by production of a number of inflammatory molecules such as cytokines, reactive oxygen species (ROS), activation of leukocyte and endothelial cells, and upregulation of adhesion molecules/chemokines. The interactions of activated leukocytes with injured endothelial cells play a crucial role in the pathogenesis of the disease (6,9,10). There is a growing body of evidence indicating that ischemic renal failure is an inflammatory disease (6,11). Antineutrophil strategies, T cell depletion, and blockade of T cell CD28-B7 co-stimulation have been reported to be beneficial in protection against I/R injury (12-15). Chemokines are 8-to 10-kd proteins that play a central role in inflammation. They regulate all of the steps that are necessary for the recruitment of leukocytes to the sites of inflammation, including leukocyte activation, adhesion, chemoattraction, and transmigration across the endothelial barrier (16 -18). Chemokines are also important regulators of T helper 1 (Th1)/Th2 responses as Th1 chemokines selectively recruit Th1 cells to sites of inflammation (19 -23). A Th1 shift has been shown to have a deleterious effect in the pathogenesis of I/R (24). The CXC chemokine receptor 3 (CXCR3) is expressed predominantly on a majority of activated inflammatory (16). A high expression of CXCR3 receptor and its ligands has been reported in different models of inflammation, including rheumatoid arthritis, multiple sclerosis lesions, type 1 diabetes, and allograft rejection (25-28). Anti-CXCR3 strategies to reduce inflammation have yielded promising results in these disease models (24,25,29 -33). The role of CXCR3 in the pathogenesis of I/R injury remains to be elucidated. Therefore, we tested the hypothesis that CXCR3 signaling plays a role in the induction of inflammation through Th1 cell infiltration, mediating renal I/R injury. Materials and Methods Animals CXCR3Ϫ/Ϫ mice were generated in Craig Gerald's laboratory (30).C57BL/6 mice, purchased from Jackson Laboratory (Bar Harbor, ME),

The pathological role of IL-18Rα in renal ischemia/reperfusion injury

“…The pathophysiological mechanisms of acute ischemic renal failure involve multiple mediators, such as proinflammatory cytokines, reactive oxygen species, adhesion molecules/chemokines, and the activation of leukocytes and endothelial cells that lead to tubular injury, endothelial dysfunction, and inflammation. [24][25][26][27] In the present study, IL-18 was observed to be upregulated in renal IRI.…”

CXCR3 Mediates Renal Th1 and Th17 Immune Response in Murine Lupus Nephritis

“…Data from experimental models further support the functional importance of the CXCR3 receptor in T cell trafficking. Involvement of CXCR3 was reported in murine models of heart allograft rejection (36), autoimmune type 1 diabetes mellitus (37), and acute renal ischemic injury (38,39). CXCR3…”

NKT Cell Activation Mediates Neutrophil IFN-γ Production and Renal Ischemia-Reperfusion Injury

“…At an early time point of renal IRI, we demonstrated an increase in the influx of CD4 ϩ T cells and NKT cells. Chemokines mediate leukocyte migration into the injured kidney and IFN-␥ modulates chemokine production, including IFN-␥-inducing protein 10 (IP-10), monokine-induced by IFN-␥, and IFN-␥-inducible T cell chemoattractant production, which bind to CXCR3 to mediate T cell migration (25) (25)(26)(27)(28)(29)(30). Our previous study showed that renal IRI up-regulated IP-10 and MIP␣, MIP1␤, MIP2, which are thought to mediate T cell and neutrophil migration (31,32).…”