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Gasdermin D deficiency aborts myeloid calcium influx to drive granulopoiesis in lupus nephritis.
- Source :
-
Cell communication and signaling : CCS [Cell Commun Signal] 2024 Jun 03; Vol. 22 (1), pp. 308. Date of Electronic Publication: 2024 Jun 03. - Publication Year :
- 2024
-
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 <superscript>+</superscript> 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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Humans
Mice
Intracellular Signaling Peptides and Proteins metabolism
Intracellular Signaling Peptides and Proteins genetics
Intracellular Signaling Peptides and Proteins deficiency
Neutrophils metabolism
Granulocytes metabolism
Myeloid Cells metabolism
Mice, Inbred C57BL
Female
Extracellular Traps metabolism
Cell Differentiation
Gasdermins
Lupus Nephritis pathology
Lupus Nephritis metabolism
Lupus Nephritis genetics
Phosphate-Binding Proteins metabolism
Phosphate-Binding Proteins genetics
Phosphate-Binding Proteins deficiency
Calcium metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1478-811X
- Volume :
- 22
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell communication and signaling : CCS
- Publication Type :
- Academic Journal
- Accession number :
- 38831451
- Full Text :
- https://doi.org/10.1186/s12964-024-01681-z