Suppressing neutrophil itaconate production attenuates Mycoplasma pneumoniae pneumonia
Cui Wang1,2, Jun Wen3, Zijun Yan1,2
1Institute of Pathogenic Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
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.
Insights
Itaconate, produced by Immune-responsive gene 1 (IRG1), exacerbates Mycoplasma pneumoniae pneumonia by impairing neutrophil function. Targeting the IRG1/itaconate pathway may offer a novel therapeutic strategy for this common respiratory infection.
Area of Science:
- Immunology
- Microbiology
- Metabolic pathways
Background:
- Mycoplasma pneumoniae is a frequent cause of community-acquired pneumonia.
- Neutrophils are key players in the host response to M. pneumoniae infection.
- The role of Immune-responsive gene 1 (IRG1) and its product itaconate in M. pneumoniae infection is not well understood.
Purpose of the Study:
- To investigate the role of the IRG1/itaconate pathway in M. pneumoniae pneumonia.
- To elucidate the mechanisms by which itaconate affects neutrophil function during M. pneumoniae infection.
- To explore the therapeutic potential of targeting the IRG1/itaconate pathway.
Main Methods:
- Utilized Irg1 knockout (KO) mice and wild-type (WT) controls for infection studies.
- Quantified bacterial burden, lactate dehydrogenase (LDH), and cytokine levels.
- Analyzed neutrophil counts and itaconate concentrations in bronchoalveolar lavage fluid (BALF).
- Performed adoptive transfer of neutrophils and administered β-glucan (an IRG1 inhibitor).
- Investigated mechanistic aspects including mitochondrial reactive oxygen species (ROS) and inflammatory signaling pathways (NF-κB, STAT1, TLR2).
Main Results:
- Itaconate acts as an endogenous pro-inflammatory metabolite during M. pneumoniae infection.
- Irg1 KO mice exhibited reduced bacterial burden, LDH, and pro-inflammatory cytokines compared to WT mice.
- Neutrophils were identified as the primary source of itaconate.
- Higher neutrophil counts correlated with increased itaconate levels in patients with severe pneumonia.
- Intervention with Irg1 KO neutrophils or β-glucan attenuated pneumonia severity.
- Itaconate was found to impair neutrophil bacterial killing and suppress neutrophil apoptosis by inhibiting mitochondrial ROS.
- M. pneumoniae infection activated IRG1 expression via TLR2-mediated NF-κB and STAT1 signaling.
Conclusions:
- The IRG1/itaconate pathway plays a significant pro-inflammatory role in M. pneumoniae pneumonia.
- Itaconate negatively impacts neutrophil function, hindering bacterial clearance and promoting inflammation.
- Targeting the IRG1/itaconate pathway presents a promising therapeutic avenue for treating M. pneumoniae pneumonia.
