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Role of CXC Chemokine Receptor 3 Pathway in Renal Ischemic Injury

Paolo Fiorina^*, Mohammed Javeed Ansari^*, Mollie Jurewicz^*, Mark Barry^*, Vincent Ricchiuti, Rex Neal Smith, Susan Shea, Terry K. Means, Hugh Auchincloss, Jr., Andrew D. Luster, Mohamed H. Sayegh^* and Reza Abdi^*

^* Transplantation Research Centre, Children’s Hospital and Brigham and Women’s Hospital, and Endocrinology Core Lab, Brigham and Women’s Hospital, Harvard Medical School, and Department of Pathology and Surgery, and Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, Massachusetts

Address correspondence to: Dr. Reza Abdi, Transplantation Research Center, Children’s Hospital and Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115. Phone: 617-525-8003; Fax: 617-732-5254; E-mail: rabdi{at}rics.bwh.harvard.edu

Received for publication September 13, 2005. Accepted for publication January 1, 2006.

Chemokines play a major role in the recruitment of leukocytes in inflammation and in the regulation of T helper 1 (Th1)/Th2 immune responses. These mechanisms have been recognized to be important in the pathogenesis of renal ischemia-reperfusion (I/R) injury. The interaction of the CXC chemokine receptor 3 (CXCR3) receptor with its ligands is a key pathogenic pathway in promoting inflammation and in enhancing Th1 immune responses. After the induction of ischemia in the mouse model of renal ischemia, an increase in intrarenal expression of CXCR3 and its ligands was observed. Compared with the wild-type (WT) mice, CXCR3-deficient mice (CXCR3^–/–) had significantly lower serum creatinine levels, better survival rate, and significantly less acute tubular necrosis and cellular infiltrates. In the kidney, intracellular staining of infiltrating cells that were recovered from kidneys revealed a lower percentage of CD4⁺IFN-⁺ cells in the CXCR3^–/– mice compared with the WT mice. Furthermore, adoptive transfer of WT CD3⁺ cells into CXCR3^–/– mice before induction of I/R injury abrogated the protection of CXCR3^–/– mice from I/R injury. It is concluded that CXCR3 plays an important role in orchestrating the recruitment of Th1 cells to the ischemic kidney and in mediating I/R injury and therefore may serve as a novel target for the therapy of I/R injury.

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