Gasdermin D deficiency aborts myeloid calcium influx to drive granulopoiesis in lupus nephritis.

Gasdermin D (GSDMD) is emerging as an important player in autoimmune diseases, but its exact role in lupus nephritis (LN) remains controversial. Here, we identified markedly elevated GSDMD in human and mouse LN kidneys, predominantly in CD11b+ myeloid cells. Global or myeloid-conditional deletion of GSDMD was shown to exacerbate systemic autoimmunity and renal injury in lupus mice with both chronic graft-versus-host (cGVH) disease and nephrotoxic serum (NTS) nephritis. Interestingly, RNA sequencing and flow cytometry revealed that myeloid GSDMD deficiency enhanced granulopoiesis at the hematopoietic sites in LN mice, exhibiting remarkable enrichment of neutrophil-related genes, significant increases in total and immature neutrophils as well as granulocyte/macrophage progenitors (GMPs). GSDMD-deficient GMPs and all-trans-retinoic acid (ATRA)-stimulated human promyelocytes NB4 were further demonstrated to possess enhanced clonogenic and differentiation abilities compared with controls. Mechanistically, GSDMD knockdown promoted self-renewal and granulocyte differentiation by restricting calcium influx, contributing to granulopoiesis. Functionally, GSDMD deficiency led to increased pathogenic neutrophil extracellular traps (NETs) in lupus peripheral blood and bone marrow-derived neutrophils. Taken together, our data establish that GSDMD deletion accelerates LN development by promoting granulopoiesis in a calcium influx-regulated manner, unraveling its unrecognized critical role in LN pathogenesis.

ST6GAL1 polymorphisms influence susceptibility and progression of IgA nephropathy in a Chinese Han population.

BACKGROUND: ST6GAL1 has been identified as a novel susceptibility gene for IgA nephropathy (IgAN) in a previous genome-wide association study. The present study is aimed at exploring whether the genetic polymorphisms of ST6GAL1 gene correlate with IgAN susceptibility, clinical phenotypes and progression in a Chinese Han population. METHODS: Twenty-six single nucleotide polymorphisms (SNPs) of ST6GAL1 were genotyped in 1000 biopsy-proven IgAN patients and 1000 control subjects of Chinese Han population using Sequenom MassARRAY iPLEX. A logistic regression analysis with age and sex as covariates was performed to evaluate the effects of ST6GAL1 gene polymorphisms on IgAN susceptibility. Kaplan-Meier method and Cox proportional hazard models were applied to analyze the associations between genetic variants and renal survival. RESULTS: We found that rs7634389 (OR = 1.24, 95 % CI = 1.02-1.50, pdominant = 0.034) and rs6784233 (OR = 1.23, 95 % CI = 1.05-1.45, padditive = 0.013; OR = 1.28, 95 % CI = 1.05-1.55, pdominant = 0.014) were associated with susceptibility of IgAN. In addition, rs7634389 was correlated with hyperuricemia (OR = 1.27, p =  0.012) and segmental glomerulosclerosis (OR = 1.21, p = 0.047) in IgAN patients. Furthermore, rs7634389 was independently associated with renal survival after adjustments for multiple confounders (hazard ratio [HR] = 0.51, 95 % CI = 0.33-0.78, p =  0.002). Haplotype analysis for ST6GAL1 polymorphisms confirmed their associations with the susceptibility to IgAN. CONCLUSIONS: Our research suggested that ST6GAL1 gene polymorphisms were implicated in IgAN susceptibility and clinical outcome in a Chinese Han population.