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

Abstract

Infiltration of T cells into the kidney is a typical feature of human and experimental lupus nephritis that contributes to renal tissue injury. The chemokine receptor CXCR3 is highly expressed on Th1 cells and is supposed to be crucial for their trafficking into inflamed tissues. In this study, we explored the functional role of CXCR3 using the MRL/MpJ-Faslpr (MRL/lpr) mouse model of systemic lupus erythematosus that closely resembles the human disease. CXCR3−/− mice were generated and backcrossed into the MRL/lpr background. Analysis of 20-wk-old CXCR3−/− MRL/lpr mice showed amelioration of nephritis with reduced glomerular tissue damage and decreased albuminuria and T cell recruitment. Most importantly, not only the numbers of renal IFN-γ-producing Th1 cells, but also of IL-17-producing Th17 cells were significantly reduced. Unlike in inflamed kidneys, there was no reduction in the numbers of IFN-γ- or IL-17-producing T cells in spleens, lymph nodes, or the small intestine of MRL/lpr CXCR3−/− mice. This observation suggests impaired trafficking of effector T cells to injured target organs, rather than the inability of CXCR3−/− mice to mount efficient Th1 and Th17 immune responses. These findings show a crucial role for CXCR3 in the development of experimental lupus nephritis by directing pathogenic effector T cells into the kidney. For the first time, we demonstrate a beneficial effect of CXCR3 deficiency through attenuation of both the Th1 and the newly defined Th17 immune response. Our data therefore identify the chemokine receptor CXCR3 as a promising therapeutic target in lupus nephritis.

Activated Protein C Attenuates Systemic Lupus Erythematosus and Lupus Nephritis in MRL-Fas(lpr) Mice

“…As such, we assume that activated protein C did not have direct effects on T and B cells, but rather that these are secondary to activated protein C-mediated suppression of dendritic cell activation. Interestingly, recombinant activated protein C did not have an effect on spleen T cell counts, and its suppressive effect was limited to Th1 and Th17 T cells, two effector T cell subpopulations that play a dominant role in the cellular component of autoimmunity in human SLE as well as in SLE of MRL-Fas(lpr) mice (20,39). Also, in a mouse model of multiple sclerosis, the amelioration of disease after activated protein C treatment was accompanied with inhibition of Th1 and Th17 cytokines (11).…”

“…Siglec-H is from eBioscience (San Diego, CA). Intracellular IFN-g and IL-17A staining was performed as described elsewhere (20). Briefly, splenocytes were isolated by standard protocols and incubated with PMA (5 ng/ml; Sigma-Aldrich) and ionomycin (1 mg/ml; Calbiochem) for 5 h. After 30 min, brefeldin A (10 mg/ml; Sigma-Aldrich) was added.…”

Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

“…2/2 MRL/lpr mice displayed nephritis with reduced albuminuria and less glomerular tissue damage, which was associated with diminished infiltration of Th1 and Th17 cells into the kidneys (44). In contrast, CXCR3-deficient NZB/W mice had reduced IgG1 titers but did not show clinical improvement (45).…”

Chemokines in Renal Injury

“…90 -92,9 CXCR3 deficiency reduces glomerular damage and T cell recruitment in crescentic glomerulone-phritis and lupus. 93,94 Most importantly, the decrease in T cell recruitment is due to reduction of both renal IFN-␥-producing Th1 cells and IL-17-producing Th17 cells. 93 As CXCR3 is expressed on the Th17 cells, reduction of Th17 cell infiltration may be related to impaired trafficking of these cells in CXCR3 null mice, rather than reduction of these cells within injured kidneys.…”

“…93,94 Most importantly, the decrease in T cell recruitment is due to reduction of both renal IFN-␥-producing Th1 cells and IL-17-producing Th17 cells. 93 As CXCR3 is expressed on the Th17 cells, reduction of Th17 cell infiltration may be related to impaired trafficking of these cells in CXCR3 null mice, rather than reduction of these cells within injured kidneys. 93 As CXCR3 is a trafficking receptor for both Th1 and Th17 cells, CXCR3 is one of the potential targets for therapy of T cell-mediated renal injury.…”