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Mitochondrial ROS-ER Stress Axis Governs IL-10 Production in Neutrophils and Regulates Inflammation in Murine
Bin Chou1, Kazunari Ishii1, Yusuke Kurihara1,2
1Department of Microbiology & Immunology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
Abstract:
Neutrophils are among the first cells to be recruited to the lungs during Chlamydia pneumoniae infection in mouse models; however, their regulatory functions are not yet fully understood. This study examined the mechanisms and significance of IL-10-producing neutrophils throughout C. pneumoniae pulmonary infection in C57BL/6 mice. Our findings revealed that infection with C. pneumoniae induces IL-10 secretion in bone marrow-derived neutrophils, depending on Toll-like receptor 2 (TLR2) activation. This process involves TLR2-dependent mitochondrial reactive oxygen species (ROS) production, which triggers the endoplasmic reticulum (ER) stress pathway, including IRE1α and subsequent Xbp1 splicing. Inhibition of this pathway or depletion of neutrophils (using the 1A8 monoclonal antibody) significantly reduces IL-10 levels in bronchoalveolar lavage fluid (BALF) in vivo. Conversely, the absence of IL-10-producing neutrophils, whether through depletion or TLR2 deficiency, leads to increased IL-12p70 and IFN-γ-positive NK cells, along with decreased regulatory T cells and M2-like macrophages. This results in a lower bacterial burden in the lungs but causes more severe pulmonary damage and decreased survival rates. These findings highlight that IL-10 produced by neutrophils via the TLR2-mitochondrial ROS-ER stress pathway is essential for modulating pulmonary immune responses and maintaining immune homeostasis during C. pneumoniae infection, thereby preventing excessive inflammation and tissue damage.
Insights
Neutrophil-derived IL-10 is crucial for immune balance during Chlamydia pneumoniae lung infections. It prevents severe lung damage and mortality by regulating inflammatory responses, despite reducing bacterial clearance.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- Neutrophils are early responders to Chlamydia pneumoniae lung infections.
- The regulatory roles of neutrophils, particularly IL-10 production, remain unclear.
Purpose of the Study:
- To investigate the mechanisms and importance of IL-10-producing neutrophils during C. pneumoniae pulmonary infection.
- To elucidate the signaling pathways involved in neutrophil IL-10 secretion.
Main Methods:
- Utilized C57BL/6 mouse models of C. pneumoniae infection.
- Investigated Toll-like receptor 2 (TLR2) activation, mitochondrial ROS production, and ER stress pathways (IRE1α/Xbp1).
- Employed neutrophil depletion (1A8 antibody) and TLR2 deficiency models.
Main Results:
- C. pneumoniae infection induced neutrophil IL-10 via TLR2, mitochondrial ROS, and ER stress.
- Inhibition of this pathway or neutrophil depletion reduced IL-10 levels.
- Lack of neutrophil IL-10 increased IL-12p70/IFN-γ NK cells but decreased Tregs and M2 macrophages.
- This led to reduced bacterial load but increased lung damage and mortality.
Conclusions:
- Neutrophil-derived IL-10 is vital for immune homeostasis during C. pneumoniae infection.
- The TLR2-ROS-ER stress pathway mediates this crucial IL-10 production.
- This pathway prevents excessive inflammation and tissue damage, improving survival.
