PDF(Pubmed)
Abstract：
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.
摘要：
GasderminD(GSDMD)正在成为自身免疫性疾病的重要参与者，但其在狼疮性肾炎（LN）中的确切作用仍存在争议。这里,我们发现人和小鼠LN肾脏中GSDMD显著升高，主要存在于CD11b+髓系细胞中。GSDMD的整体或髓样条件性缺失被证明会加剧患有慢性移植物抗宿主（cGVH）疾病和肾毒性血清（NTS）肾炎的狼疮小鼠的全身性自身免疫和肾损伤。有趣的是,RNA测序和流式细胞术显示髓样GSDMD缺乏增强LN小鼠造血位点的粒细胞生成,表现出显著富集的中性粒细胞相关基因，总的和未成熟的嗜中性粒细胞以及粒细胞/巨噬细胞祖细胞(GMPs)显著增加。进一步证明了GSDMD缺陷型GMPs和全反式维甲酸（ATRA）刺激的人早幼粒细胞NB4与对照组相比具有增强的克隆形成和分化能力。机械上,GSDMD敲除通过限制钙流入促进自我更新和粒细胞分化，有助于粒细胞生成。功能上,GSDMD缺乏导致狼疮外周血和骨髓源性中性粒细胞中致病性中性粒细胞胞外陷阱（NETs）增加。一起来看,我们的数据证实GSDMD缺失通过以钙流入调节的方式促进粒细胞生成来加速LN的发育，揭示其在LN发病机制中的未被识别的关键作用。
