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Variants in STAT4 are associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. How disease-associated variants affect STAT4 expression, in particular in CD4 T cells where STAT4 plays an essential role, is unknown.We compared Th1 differentiation between naïve CD4 T cells from healthy donors (HD) homozygous for the risk (R/R) or non-risk (NR/NR) alleles. We analyzed epigenetic marks in STAT4 and evaluated the relevance of its third intron. We assessed the consequences of Stat4 overexpression in vivo. We analyzed the effects of the STAT4 genotype in patients with lupus nephritis.Naïve CD4 T cells from NR/NR HD, downregulated STAT4 in response to IL-12. In contrast, cells from R/R HD maintained high levels. R/R cells exhibited higher abundance of transcriptionally active STAT4 and increased IFN-γ production. Accordingly, R/R HD exhibited a stronger induction of local active enhancer marks. Genetic editing confirmed the presence of a negative regulatory region in the STAT4 third intron, where most of the SLE-associated STAT4 SNPs are located. In vivo forced expression demonstrated that increases in Stat4 levels in T cells enhanced glomerulonephritis. Accordingly, the R/R genotype was associated with suboptimal response to treatment and with worse clinical outcomes in patients with proliferative lupus nephritis.The SLE-associated STAT4 haplotype is associated with abnormal IL-12-mediated STAT4 transcriptional regulation. Carriers of the risk variant exhibit exaggerated CD4 pro-inflammatory capacities that, in the context of SLE, contribute to a more severe disease. R/R patients may benefit from blockade of the IL-12-STAT4 pathway. This article is protected by copyright. All rights reserved.

Acute kidney injury (AKI) is a public health problem worldwide. Sirtuins are a family of seven NAD+-dependent deacylases, Overexpression of Sirtuin 1, 3, and 5 protect against AKI. However, the role of Sirtuin 7 (Sirt7) in AKI is not known. Here, we analyzed how Sirt7 deficient mice (KO-Sirt7) were affected by AKI. As expected, wild-type and Sirt7 heterozygotes mice that underwent renal ischemia/reperfusion (IR) exhibited the characteristic hallmarks of AKI: renal dysfunction, tubular damage, albuminuria, increased oxidative stress, and renal inflammation. In contrast, the KO-Sirt7+IR mice were protected from AKI, exhibiting lesser albuminuria and reduction in urinary biomarkers of tubular damage, despite similar renal dysfunction. The renoprotection in the Sirt7-KO+IR group was associated with reduced kidney weight, minor expression of inflammatory cytokines and less renal infiltration of inflammatory cells. This anti-inflammatory effect was related to diminished p65 expression and in its active phosphorylation, as well as by a reduction in p65 nuclear translocation. Sirt7 deficient mice are protected from AKI, suggesting that this histone deacetylase promotes tubular damage and renal inflammation. Therefore, our findings indicate that Sirt7 inhibitors may be an attractive therapeutic target to reduce NFκB signaling.

Purpose of review The aim of this review is to discuss recent developments in our understanding of how systemic lupus erythematosus (SLE)-associated genes contribute to autoimmunity. Recent findings Gene-function studies have revealed mechanisms through which SLE-associated alleles of IFIH1, TNFAIP3, IRF5, and PRDM1 likely contribute to the development of autoimmunity. Novel research has identified Mac-1 (encoded by ITGAM), CaMK4, and iRhom2 as plausible therapeutic targets in lupus nephritis. Summary The work discussed in this review has broad implications for our understanding of the pathogenesis of SLE and for the development of novel therapeutic strategies.