CCR2 Enhances Anti-Intracellular Bacterial Infection by Modulating Macrophage Pyroptosis to Rebalance Th Immune...

Area of Science:

• Immunology
• Microbiology
• Cell Biology

Background:

• Intracellular bacterial infections like Chlamydia pose challenges due to antibiotic resistance and tissue damage.
• Macrophages, derived from monocytes, are key in host defense but their regulation during infection is complex.
• The chemokine receptor CCR2 influences monocyte migration, but its role in macrophage function and immune balance is not fully understood.

Purpose of the Study:

• To investigate how CCR2 regulates macrophage function during Chlamydia respiratory infection.
• To determine CCR2's role in balancing protective Th1 immunity versus pathological Th2/Th17 immunity.
• To elucidate the mechanisms by which CCR2 influences macrophage phenotype and inflammatory responses.

Main Methods:

• Studied CCR2-deficient mice infected with Chlamydia.
• Analyzed pulmonary monocyte infiltration and macrophage differentiation.
• Utilized in vitro bone marrow-derived macrophages (BMDMs) stimulated with C. muridarum.
• Co-cultured BMDMs with CD4+ T cells to assess T cell polarization.

Main Results:

• CCR2 deficiency reduced monocyte infiltration and shifted macrophages to an M2-like phenotype.
• CCR2 deficiency impaired macrophage endocytosis, survival, and promoted ROS production, NLRP3 inflammasome activation, and pyroptosis.
• In vitro, Ccr2-deficient BMDMs showed impaired migration, M1 polarization, and enhanced pyroptosis.
• CCR2 deficiency inhibited Th1 differentiation and promoted Th2/Th17 responses in co-cultures.

Conclusions:

• CCR2 orchestrates monocyte-macrophage function by promoting M1 polarization and inhibiting NLRP3/Caspase-3/GSDME pyroptosis.
• CCR2 rebalances Th1/Th2/Th17 immunity, enhancing bacterial clearance and reducing immunopathology.
• Targeting CCR2 could be a strategy to improve treatment outcomes for Chlamydia infections.