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- Title
Gasdermin D deficiency aborts myeloid calcium influx to drive granulopoiesis in lupus nephritis.
- Authors
Shen, Jiani; Li, Feng; Han, Xu; Fu, Dongying; Xu, Yiping; Zhu, Changjian; Liang, Zhou; Tang, Ziwen; Zheng, Ruilin; Hu, Xinrong; Lin, Ruoni; Pei, Qiaoqiao; Nie, Jing; Luo, Ning; Li, Xiaoyan; Chen, Wei; Mao, Haiping; Zhou, Yi; Yu, Xueqing
- 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.
- Subjects
LUPUS nephritis; MYELOID cells; NEPHROTOXICOLOGY; NEUTROPHILS; CALCIUM channels; CALCIUM; RNA sequencing
- Publication
Cell Communication & Signaling, 2024, Vol 22, Issue 1, p1
- ISSN
1478-811X
- Publication type
Article
- DOI
10.1186/s12964-024-01681-z