IL-12 Signaling Promotes Podocyte Senescence in Lupus Nephritis.

Authors

Chaohuan Guo, Rong Fu, Wenliang Pan, Wei Li, Hao Li, Limor Rubin, Hyshem H Lancia, Joel Henderson, Shuoshuo Wang, Sheethal Umesh Nagalakshmi, Antonella Arruda de Amaral, Ioannis Vlachos, Reza Abdi, Maria G Tsokos, George C Tsokos

Published in

Arthritis & rheumatology (Hoboken, N.J.). Aug 24, 2026. Epub Aug 24, 2026.

Abstract

Podocyte injury drives proteinuria and disease progression in lupus nephritis (LN), yet the mechanisms underlying podocyte dysfunction remain incompletely understood.
Sera from 39 SLE patients including 15 patients with LN and 13 healthy controls were collected. Levels of IL-12 were measured by enzyme-linked immunosorbent assay. Expression of IL-12 receptors (IL-12R) was assessed by immunofluorescence staining. Immortalized human podocyte cell line was used for in vitro study. The podocyte conditional knockout of Il12rb1 mice including B6.Il12rb1^fl/flNphs2^cre mice and B6.lpr.Il12rb1^fl/flNphs2^cre mice were generated. Accelerated lupus model and nephrotoxic nephritis model were induced. B6.Il12rb1^fl/fl and B6.lpr.Il12rb1^fl/fl mice were used as control.
Serum levels of IL-12 were elevated in patients with LN (p=0.006) and in lupus-prone mice (p=0.041). Expression of the IL-12R was increased in podocytes in both human and murine LN. IL-12 stimulation induced the phosphorylation of calcium/calmodulin-dependent protein kinase 4 (CaMK4) and signal transducer and activator of transcription 4 (STAT4), causing mitochondrial dysfunction and increased reactive oxygen species accumulation leading to accelerated podocyte senescence, senescence-associated secretory phenotype and cytoskeleton disorganization. Podocyte-specific deletion of Il12rb1 attenuated podocyte senescence, ameliorated glomerular injury, and reduced proteinuria in both lupus-prone mice and normal mice injected with a nephrotoxic serum.
Our findings identify IL-12 signaling as an important mediator of podocyte senescence in LN and suggest that targeting the IL-12-IL-12R axis may offer future therapeutic approaches to preserve podocytes and attenuate LN.

PMID:
42635289
Bibliographic data and abstract were imported from PubMed on 24 Aug 2026.

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