Suppressing neutrophil itaconate production attenuates Mycoplasma pneumoniae pneumonia.

IF 5.5 1区 医学 Q1 MICROBIOLOGY
PLoS Pathogens Pub Date : 2024-11-05 eCollection Date: 2024-11-01 DOI:10.1371/journal.ppat.1012614
Cui Wang, Jun Wen, Zijun Yan, Yujun Zhou, Zhande Gong, Ying Luo, Zhenkui Li, Kang Zheng, Haijun Zhang, Nan Ding, Chuan Wang, Cuiming Zhu, Yimou Wu, Aihua Lei
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引用次数: 0

Abstract

Mycoplasma pneumoniae is a common cause of community-acquired pneumonia in which neutrophils play a critical role. Immune-responsive gene 1 (IRG1), responsible for itaconate production, has emerged as an important regulator of inflammation and infection, but its role during M. pneumoniae infection remains unknown. Here, we reveal that itaconate is an endogenous pro-inflammatory metabolite during M. pneumoniae infection. Irg1 knockout (KO) mice had lower levels of bacterial burden, lactate dehydrogenase (LDH), and pro-inflammatory cytokines compared with wild-type (WT) controls after M. pneumoniae infection. Neutrophils were the major cells producing itaconate during M. pneumoniae infection in mice. Neutrophil counts were positively correlated with itaconate concentrations in bronchoalveolar lavage fluid (BALF) of patients with severe M. pneumoniae pneumonia. Adoptive transfer of Irg1 KO neutrophils, or administration of β-glucan (an inhibitor of Irg1 expression), significantly attenuated M. pneumoniae pneumonia in mice. Mechanistically, itaconate impaired neutrophil bacterial killing and suppressed neutrophil apoptosis via inhibiting mitochondrial ROS. Moreover, M. pneumoniae induced Irg1 expression by activating NF-κB and STAT1 pathways involving TLR2. Our data thus identify Irg1/itaconate pathway as a potential therapeutic target for the treatment of M. pneumoniae pneumonia.

抑制中性粒细胞产生伊它康酸可减轻肺炎支原体肺炎。
肺炎支原体是社区获得性肺炎的常见病因,中性粒细胞在其中发挥着关键作用。负责产生伊塔康酸的免疫反应基因 1(IRG1)已成为炎症和感染的重要调节因子,但它在肺炎支原体感染过程中的作用仍不清楚。在这里,我们揭示了它康酸是肺炎霉菌感染过程中的一种内源性促炎症代谢产物。与野生型(WT)对照组相比,Irg1基因敲除(KO)小鼠感染肺炎霉菌后的细菌负荷、乳酸脱氢酶(LDH)和促炎细胞因子水平较低。中性粒细胞是小鼠感染肺炎霉菌后产生伊他康酸的主要细胞。中性粒细胞数量与重症肺炎双球菌肺炎患者支气管肺泡灌洗液(BALF)中伊他康酸浓度呈正相关。采用Irg1 KO中性粒细胞转移或服用β-葡聚糖(Irg1表达抑制剂)可显著减轻小鼠的肺炎霉菌肺炎。从机理上讲,伊塔康酸可通过抑制线粒体 ROS 来削弱中性粒细胞对细菌的杀伤力并抑制中性粒细胞的凋亡。此外,肺炎霉菌通过激活涉及 TLR2 的 NF-κB 和 STAT1 通路诱导 Irg1 的表达。因此,我们的数据确定了 Irg1/itaconate 通路是治疗 M. pneumoniae 肺炎的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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