Suppressing neutrophil itaconate production attenuates Mycoplasma pneumoniae pneumonia

• Published in: PLoS pathogens Vol. 20; no. 11; p. e1012614
• Main Authors: Wang, Cui, Wen, Jun, Yan, Zijun, Zhou, Yujun, Gong, Zhande, Luo, Ying, Li, Zhenkui, Zheng, Kang, Zhang, Haijun, Ding, Nan, Wang, Chuan, Zhu, Cuiming, Wu, Yimou, Lei, Aihua
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.11.2024; Public Library of Science (PLoS)
• Subjects: Analysis; Bacterial pneumonia; Care and treatment; Cytokines; Diagnosis; Health aspects; Infection control; Measurement; Methods; Neutrophils; Pneumonia; Risk factors; China
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012614

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.