Thiolutin, a novel NLRP3 inflammasome inhibitor, mitigates IgA nephropathy in mice

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-13 DOI:10.1016/j.intimp.2025.114440

Yun Zhang, Shuhan Shi, Changda Lin, Quanzuan Zeng, Lishuang Che, Yuangen Li, Weiyuan Lin

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引用次数: 0

Abstract

NLRP3 inflammasome plays a key role in IgA Nephropathy (IgAN) pathogenesis. Thiolutin (THL) is an NLRP3 inflammasome inhibitor with anti-inflammatory effects, but its role in IgAN is unclear. This study aimed to evaluate the protective efficacy of THL in IgAN mice, alongside assessing its inhibitory mechanisms. IgAN was induced by administration of bovine serum albumin combined with Staphylococcal Enterotoxin B in mice, followed by THL treatment. Kidney injury biomarkers, inflammatory cytokines, histological changes and the NLRP3 inflammasome pathway were assessed. The effect of THL on pyroptosis and action site on inflammasome was examined in J774A.1 cells, and co-immunoprecipitation was used to study specific protein interactions. In IgAN mice, THL treatment significantly reduced renal dysfunctional markers and histological injury without affecting hepatic function, accompanied by decreased serum IgA levels, renal IgA deposition and pro-inflammatory cytokine accumulation via regulating the mRNA and protein expression of key inflammasome components. It also attenuated pyroptosis and NLRP3 inflammasome activation instead of priming in macrophages, via disturbing the combination of NLRP3 with apoptosis-associated speck-like protein and NIMA-Related Kinase 7. THL has significant anti-inflammatory and renal protective effects in IgAN via inhibiting the NLRP3 inflammasome pathway. Its selective impact on the activation and assembly of the inflammasome, without affecting priming, highlights its potential as a targeted therapeutic agent in IgAN management.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.