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 CCL2Ϫ/Ϫ 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 CXCL10Ϫ/Ϫ MRL-Fas lpr mice, and CXCL10 Ϫ/Ϫ C57BL/6 mice were not protected from nephrotoxic serum nephritis compared with WT mice. Because CXCR3 engages with the ligand CXCL9, CXCR3 Ϫ/Ϫ , CXCL9 Ϫ/Ϫ , and CXCL10 Ϫ/Ϫ 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 Ϫ/Ϫ and CXCL9 Ϫ/Ϫ mice but not in CXCL10 Ϫ/Ϫ mice. With nephrotoxic serum nephritis, CXCR3 Ϫ/Ϫ and CXCL9 Ϫ/Ϫ 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 or CXCR3 may be a potential therapeutic target for human immune-mediated kidney diseases.

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

“…In this study, we show for the first time that CXCR3 deficiency improves renal outcome in the MRL/lpr model of lupus nephritis, not only by reducing the number of renal Th1 cells, but also by almost completely abolishing Th17 cell infiltration. In agreement with published studies (40,41), renal mRNA expression of all three CXCR3 ligands, Mig/CXCL9, IP-10/ CXCL10, and ITAC/CXCL11, as well as CXCR3 mRNA, increased with progression of nephritis in MRL/lpr animals from 10 wk of age. At the time of sacrifice (20 wk of age), intrarenal chemokine levels of all CXCR3 ligands were slightly reduced in MRL/lpr CXCR3 Ϫ/Ϫ mice.…”

“…There is still a lack of evidence to support a protective role of interference with the CXCR3 receptor-ligand axis in chronic renal autoimmune disease, such as the lupus nephritis of MRL/lpr mice. As in NTN, IP10/CXCL10 deficiency did not lead to improvement of the clinical course of glomerulonephritis in this murine model of human lupus nephritis (40). The influence of CXCR3 deficiency has not been studied to date.…”

“…Because the MCP-1/CCL2 production by resident renal cells is stimulated by IL-17 (11), reduced expression might be a result of impaired renal Th17 cell infiltration. We cannot exclude, however, that CXCR3 expression on activated monocytes also contributes to the trafficking of this pathogenic cell population into the nephritic kidney, as was recently reported (40).…”

“…These observations have meanwhile been confirmed by a study conducted by another group that shows improved renal outcome in mice deficient in the CXCR3 or its ligand Mig/CXCL9 in NTN. Surprisingly, however, IP10/CXCL10 deficiency did not alter renal pathology (40). There is still a lack of evidence to support a protective role of interference with the CXCR3 receptor-ligand axis in chronic renal autoimmune disease, such as the lupus nephritis of MRL/lpr mice.…”

CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN

“…31,32 The recruitment of CXCR3 + T cells into the kidney was shown in human and experimental GN, 33,34 and subsequent studies showed that CXCR3 mediates T effector cell recruitment and tissue injury in experimental models of crescentic GN. 35,36 These studies show the potential beneficial effect of nonselective CXCR3 blockade in crescentic GN. Our results suggest, however, that specific targeting of CXCR3 on T H 1 cells or the blockade of T H 1-specific mediators would be even more effective than pan-CXCR3 neutralization in T H 1-driven inflammatory diseases.…”