TLR4-mediated endoplasmic reticulum stress regulates pyroptosis in macrophages infected with the Bacillus Calmette-Guérin mycobacterial

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-09 DOI:10.1016/j.intimp.2025.114346

Xueyi Nie , Shen'ao Miao , Yuxin Hou , Yabo Ma , Mengyuan Li , Yueyang Liu , Yi Yang , Jinrui Xu , Yujiong Wang

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引用次数: 0

Abstract

Tuberculosis results from Mycobacterium tuberculosis (Mtb) infection. Immune responses controlled by Toll-like receptor 4 (TLR4) are closely associated with the host response to pathogens, including Mtb. NLRP3 inflammasome-mediated pyroptosis forms a significant part of the inflammatory response during Mtb infection, and endoplasmic reticulum stress (ERS) is implicated in the activation of the NLRP3 inflammasome. Here, the function of TLR4 in macrophage pyroptosis induced by infection with the Bacillus Calmette-Guérin (BCG) mycobacterial strain was investigated. It was found that infection with BCG activated TLR4 signaling, induced ERS and subsequent NLRP3 inflammasome activation, leading to pyroptosis in mouse lung tissues. The TLR4 inhibitor TAK 242 inhibited the ERS onset, NLRP3 inflammasome stimulation, and pyroptosis, while the ERS inhibitor TUDCA blocked both inflammasome activation and pyroptosis, and the NLRP3 inhibitor MCC950 specifically inhibited pyroptosis. Furthermore, TAK 242, TUDCA, and MCC950 all exacerbated lung injury caused by BCG infection and promoted BCG survival. Similarly, after in BCG-infected THP-1 macrophages, TLR4 signaling was found to mediate NLRP3 inflammasome activation through ERS, thereby inducing pyroptosis. In summary, BCG infection leads to macrophage pyroptosis via the TLR4/ERS/NLRP3 inflammasome signaling axis, providing new insights for further research into the pathogenesis and treatment of tuberculosis.

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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.