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CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease.

ABSTRACT: Chemokines are instrumental in macrophage- and T cell-dependent diseases. The chemokine CCL2 promotes kidney disease in two models of immune-mediated nephritis (MRL-Fas(lpr) mice and the nephrotoxic serum nephritis model), but evidence suggests that multiple chemokines are involved. For identification of additional therapeutic targets for immune-mediated nephritis, chemokine ligands and receptors in CCL2-/- and wild-type (WT) MRL-Fas(lpr) kidneys were profiled. The focus was on intrarenal chemokine ligand/receptor pairs that were highly upregulated downstream of CCL2; the chemokine CXCL10 and its cognate receptor, CXCR3, stood out as potential therapeutic targets. However, renal disease was not suppressed in CXCL10-/- MRL-Fas(lpr) mice, and CXCL10-/- C57BL/6 mice were not protected from nephrotoxic serum nephritis compared with WT mice. Because CXCR3 engages with the ligand CXCL9, CXCR3-/- , CXCL9-/- , and CXCL10-/- B6 mice were compared with WT mice with nephrotoxic serum nephritis. Kidney disease, measured by loss of renal function and histopathology, was suppressed in both CXCR3-/- and CXCL9-/- mice but not in CXCL10-/- mice. With nephrotoxic serum nephritis, CXCR3-/- and CXCL9-/- mice had fewer intrarenal activated T cells and activated macrophages. Both IgG glomerular deposits and antigen-specific IgG in serum were reduced in these mice, suggesting that although CXCR3 and CXCL9 initiate nephritis through cell-mediated events, renal inflammation may be sustained by their regulation of IgG. It is concluded that specific blockade of CXCL9

SUBMITTER: Menke J

PROVIDER: S-EPMC2396941 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease.

Menke Julia J Zeller Geraldine C GC Kikawada Eriya E Means Terry K TK Huang Xiao R XR Lan Han Y HY Lu Bao B Farber Joshua J Luster Andrew D AD Kelley Vicki R VR

Journal of the American Society of Nephrology : JASN 20080312 6

Chemokines are instrumental in macrophage- and T cell-dependent diseases. The chemokine CCL2 promotes kidney disease in two models of immune-mediated nephritis (MRL-Fas(lpr) mice and the nephrotoxic serum nephritis model), but evidence suggests that multiple chemokines are involved. For identification of additional therapeutic targets for immune-mediated nephritis, chemokine ligands and receptors in CCL2-/- and wild-type (WT) MRL-Fas(lpr) kidneys were profiled. The focus was on intrarenal chemok ...[more]

PMID: 18337479

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Project description:Coxsackievirus A2 (CVA2) is an emerging pathogen that results in hand-foot-and-mouth disease (HFMD) outbreaks. Systemic inflammatory response and central nervous system inflammation are the main pathological features of fatal HFMD. However, the immunopathogenesis of CVA2 infection is poorly understood. We first detected the transcriptional levels of 81 inflammation-related genes in neonatal mice with CVA2 infection. Remarkably, CVA2 induced higher expression of chemokine (C-X-C motif) ligand 10 (CXCL10) in multiple organs and tissues. CXCL10 acts through its cognate receptor chemokine (C-X-C motif) receptor 3 (CXCR3) and regulates immune responses. CXCL10/CXCR3 activation contributes to the pathogenesis of many inflammatory diseases. Next, we found CXCL10 and CXCR3 expression to be significantly elevated in the organs and tissues from CVA2-infected mice at 5 days postinfection (dpi) using immunohistochemistry (IHC). To further explore the role of CXCL10/CXCR3 in CVA2 pathogenesis, an anti-CXCR3 neutralizing antibody (αCXCR3) or IgG isotype control antibody was used to treat CVA2-infected mice on the same day as infection and every 24 h until 5 dpi. Our results showed that αCXCR3 therapy relieved the clinical manifestations and pathological damage and improved the survival rate of CVA2-infected mice. Additionally, αCXCR3 treatment reduced viral loads and reversed the proinflammatory cytokine (interleukin 6 [IL-6], tumor necrosis factor alpha [TNF-α], and IL-1β) expression, apoptosis, and inflammatory cell infiltration induced by CVA2. Collectively, our study presents evidence for the involvement of the CXCL10/CXCR3 axis in CVA2 pathogenesis. The activation of CXCL10/CXCR3 contributes to CVA2 pathogenesis by inducing apoptosis, proinflammatory cytokine expression, and inflammatory cell infiltration, which can be reversed by αCXCR3 therapy. This study provides new insight into the pathogenesis of HFMD, which has an important guiding significance for the treatment of HFMD. IMPORTANCE Systemic inflammatory response and central nervous system inflammation are the main pathological features of fatal HFMD cases. We detected the expression of 81 inflammation-related genes and found higher expression of CXCL10 in CVA2-infected mice. Next, we confirmed CXCL10/CXCR3 activation using immunohistochemistry and found that anti-CXCR3 neutralizing antibody (αCXCR3) therapy could relieve the clinical manifestations and pathological damage and improve the survival rate of CVA2-infected mice. Additionally, αCXCR3 treatment reduced viral loads and reversed the proinflammatory cytokine (IL-6, TNF-α, and IL-1β) expression, apoptosis, and inflammatory cell infiltration induced by CVA2. Collectively, our study presents the first evidence for the involvement of the CXCL10/CXCR3 axis in CVA2 pathogenesis. The activation of CXCL10/CXCR3 contributes to CVA2 pathogenesis via inducing apoptosis, proinflammatory cytokine expression, and inflammatory cell infiltration, which can be reversed by αCXCR3 therapy. This study provides new insight into the pathogenesis of HFMD, which has an important guiding significance for the treatment of HFMD.

Dataset Information

CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease.

Publications

CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease.

Similar Datasets

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