Neutrophil trafficking to sites of inflammation is essential for the defense against bacterial and fungal infections, but also contributes to tissue damage in T H 17-mediated autoimmunity. This process is regulated by chemokines, which often show an overlapping expression pattern and function in pathogen-and autoimmune-induced inflammatory reactions. Using a murine model of crescentic GN, we show that the pathogenic T H 17/IL-17 immune response induces chemokine (C-X-C motif) ligand 5 (CXCL5) expression in kidney tubular cells, which recruits destructive neutrophils that contribute to renal tissue injury. By contrast, CXCL5 was dispensable for neutrophil recruitment and effective bacterial clearance in a murine model of acute bacterial pyelonephritis. In line with these findings, CXCL5 expression was highly upregulated in the kidneys of patients with ANCA-associated crescentic GN as opposed to patients with acute bacterial pyelonephritis. Our data therefore identify CXCL5 as a potential therapeutic target for the restriction of pathogenic neutrophil infiltration in T H 17-mediated autoimmune diseases while leaving intact the neutrophil function in protective immunity against invading pathogens.

The Th17 immune response appears to contribute to the pathogenesis of human and experimental crescentic GN, but the cell types that produce IL-17A in the kidney, the mechanisms involved in its induction, and the IL-17A-mediated effector functions that promote renal tissue injury are incompletely understood. Here, using a murine model of crescentic GN, we found that CD4 + T cells, gd T cells, and a population of CD3 + CD4 2 CD8 2 gdT cell receptor 2 NK1.1 2 T cells all produce IL-17A in the kidney. A time course analysis identified gd T cells as a major source of IL-17A in the early phase of disease, before the first CD4 + Th17 cells arrived. The production of IL-17A by renal gd T cells depended on IL-23p19 signaling and retinoic acid-related orphan receptor-gt but not on IL-1b or IL-6. In addition, depletion of dendritic cells, which produce IL-23 in the kidney, reduced IL-17A production by renal gd T cells. Furthermore, the lack of IL-17A production in gd T cells, as well as the absence of all gd T cells, reduced neutrophil recruitment into the kidney and ameliorated renal injury. Taken together, these data suggest that gd T cells produce IL-17A in the kidney, induced by IL-23, promoting neutrophil recruitment, and contributing to the immunopathogenesis of crescentic GN.

Chemokines and chemokine receptors are implicated in regulatory T cell (Treg) trafficking to sites of inflammation and suppression of excessive immune responses in inflammatory and autoimmune diseases; however, the specific requirements for Treg migration into the inflamed organs and the positioning of these cells within the tissue are incompletely understood. Here, we report that Tregs expressing the T H 1-associated chemokine receptor CXCR3 are enriched in the kidneys of patients with ANCA-associated crescentic GN and colocalize with CXCR3 + effector T cells.

CD4+ T cells play a pivotal role in the pathogenesis of autoimmune disease, including human and experimental crescentic GN. Micro-RNAs (miRs) have emerged as important regulators of immune cell development, but the impact of miRs on the regulation of the CD4 + T cell immune response remains to be fully clarified. Here, we report that miR-155 expression is upregulated in the kidneys of patients with ANCAassociated crescentic GN and a murine model of crescentic GN (nephrotoxic nephritis). To elucidate the potential role of miR-155 in T cell-mediated inflammation, nephritis was induced in miR-155 2/2 and wildtype mice. The systemic and renal nephritogenic T H 17 immune response decreased markedly in nephritic miR-155 2/2 mice. Consistent with this finding, miR-155-deficient mice developed less severe nephritis, with reduced histologic and functional injury. Adoptive transfer of miR-155 2/2 and wild-type CD4 + T cells into nephritic recombination activating gene 1-deficient (Rag-1 2/2 ) mice showed the T cell-intrinsic importance of miR-155 for the stability of pathogenic T H 17 immunity. These findings indicate that miR-155 drives the T H 17 immune response and tissue injury in experimental crescentic GN and show that miR-155 is a potential therapeutic target in T H 17-mediated diseases.