C/EBPβ isoform‐specific regulation of podocyte pyroptosis in lupus nephritis‐induced renal injury

Abstract

As an essential factor in the prognosis of systemic lupus erythematosus (SLE), lupus nephritis (LN) can accelerate the rate at which patients with SLE can transition to chronic kidney disease or even end‐stage renal disease. Podocytes now appear to be a possible direct target in LN in addition to being prone to collateral damage from glomerular capillary lesions induces by immune complexes and inflammatory processes. The NLRP3 inflammasome is regulated by CCAAT/enhancer‐binding protein β (C/EBPβ), which is involved in the pathogenesis of SLE. However, the role and mechanism of C/EBPβ in LN remain unclear. In this investigation, glomerular podocytes treated with LN serum and MRL/lpr mice were employed as in vivo and in vitro models of LN, respectively. In vivo, the expression of C/EBPβ isoforms was detected in kidney specimens of humans and mice with LN. Then we assessed the effect of C/EBPβ inhibition on renal structure and function by injecting RNAi adeno‐associated virus of C/EBPβ shRNA into MRL/lpr mice. In vitro, glomerular podocytes were treated with LN serum and C/EBPβ siRNA to explore the role of C/EBPβ in the activation of the AIM2 inflammasome and podocyte injury. C/EBPβ‐LAP and C/EBPβ‐LIP were significantly overexpressed in kidney tissue samples from LN patients and mice, and C/EBPβ inhibition significantly alleviated renal function damage and ameliorated renal structural deficiencies. Inflammatory pathways downstream from the AIM2 inflammasome could be suppressed by C/EBPβ knockdown. Furthermore, the upregulation of C/EBPβ‐LAP could activate the AIM2 inflammasome and podocyte pyroptosis by binding to the promoters of AIM2 and CASPASE1 to enhance their expression, and the knockdown of AIM2 or (and) caspase‐1 reversed the effects of C/EBPβ‐LAP overexpression. Interestingly, C/EBPβ‐LIP overexpression could transcriptionally inhibit IRAG and promote Ca2+ release‐mediated activation of the AIM2 inflammasome. This finding suggests that C/EBPβ is not only involved in the regulation of the expression of key proteins of the AIM2 inflammasome but also affects the polymerization of key proteins of the AIM2 inflammasome through the regulation of Ca2+ release. In conclusion, this study provides a new idea for studying the regulatory mechanism of C/EBPβ and provides a theoretical basis for the early diagnosis and treatment of LN in the future. © 2023 The Pathological Society of Great Britain and Ireland.

Transcription Factors in the Pathogenesis of Lupus Nephritis and Their Targeted Therapy

“…CEBPB mRNA expression was significantly elevated in PBMCs from a cohort of 20 SLE patients compared to 20 gender/age-matched healthy controls [38]. Further studies demonstrated that CEBPB expression was also significantly elevated in LN patients and possibly positively associated with disease progression [39,40]. Interestingly, higher-CEBPB SLE patients tend to have a high titer of certain autoAbs (anti-Sm, anti-SNP, or ANA).…”

“…They then demonstrated that lentiviral shRNA-CEBPB mediated CEBPB knockdown in MRL/lpr LN mice reduced renal pathogenesis and improved renal function [42]. LN was similarly improved in MRL/lpr mice treated with the adeno-associated virus of CEBPB shRNA [39,40]. Collectively, studies suggest that three possible mechanisms are linked to the pathological role of CEBPB in LN: (1) CEBPB enhances NLRP3 inflammasome activation because the inhibition of CEBPB expression is associated with decreased NLRP3 levels [42].…”

“…CEBPB-activated basic leucine zipper and W2 domain-containing protein 1 (BZW1) promotes endoplasmic reticulum stress-amplified macrophage inflammatory responses via eukaryotic initiation factor 2 alpha (elF2α) phosphorylation [39]. (3) CEBPB activates absent in melanoma 2 (AIM2, an IFN-inducible protein) inflammasome and podocyte pyroptosis by binding to the promoters of AIM2 and CASPASE1 to enhance their expression, and the knockdown of AIM2 or (and) caspase-1 reversed the effects of CEBPB overexpression [40].…”

Podocyte injury and death: New insights into lupus nephritis pathogenesis and therapy

“…Among canonical programmed cell death pathways, apoptosis stands out as the predominant type, although it occasionally intersects with others, notably necroptosis and pyroptosis. 92,111,112 Both necroptosis and pyroptosis are inflammation-inducible pathways that feature a loss of plasma integrity and are characterized by a cascade of signals including MLKL and inflammasome activation, respectively. 71 Additionally, in the absence of concrete evidence regarding the occurrence of ferroptosis in LN podocytes, additional findings are needed to conclusively understand podocyte dysfunction in LN.…”

“…Furthermore, upregulation of the CCAAT/enhancer-binding protein β (C/ EBP-β) isoform was observed in LN patients and MRL/ lpr mice, while the NLRP3 inflammasome is regulated by C/EBP-β, indicating that it may regulate podocyte pyroptosis. 92 The inflammatory factors released by podocyte pyroptosis induce the proliferation of mesangial cells and the extensive secretion of collagen. 93 These converging lines of evidence underscore the central role of podocyte pyroptosis in LN.…”