IL10 trains macrophage profibrotic function after lung injury

Area of Science:

• Immunology
• Pulmonary Medicine
• Cell Biology

Background:

• Monocyte-derived macrophages (moMacs) are crucial immune cells involved in tissue repair and fibrosis.
• The precise mechanisms regulating moMac polarization and profibrotic functions remain incompletely understood.
• Platelet-derived growth factor A (Pdgfa) is implicated in fibrotic processes.

Purpose of the Study:

• To investigate the role of moMac-derived Pdgfa in bleomycin-induced lung fibrosis.
• To elucidate the regulatory pathways, particularly Interleukin-10 (IL10), involved in moMac polarization and profibrotic function.

Main Methods:

• Utilized Cx3cr1-CreERT2 mice for targeted deletion of Pdgfa in moMacs.
• Administered bleomycin to induce lung fibrosis in mouse models.
• Investigated Pdgfa induction by IL10 in both mouse and human moMacs in vitro.
• Analyzed single-cell RNA sequencing data from human fibrotic lungs.
• Employed IL10-GFP reporter mice to track IL10-expressing cells.
• Used Csf1r-Cre: IL10ra fl/fl mice to delete IL10 receptor alpha (IL10ra) in myeloid cells.

Main Results:

• Deletion of Pdgfa in moMacs reduced bleomycin-induced lung fibrosis.
• IL10 robustly induced Pdgfa expression in both mouse and human moMacs.
• High IL10 receptor alpha (IL10ra) expression was found in moMacs from human fibrotic lungs.
• IL10-expressing cells increased and colocalized with moMacs after injury.
• Deletion of IL10ra in myeloid cells decreased Pdgfa expression in moMacs and attenuated lung fibrosis.

Conclusions:

• Revealed a novel IL10-dependent pathway for macrophage polarization.
• Demonstrated that IL10 drives moMacs to express Pdgfa, contributing to fibroblast activation and lung fibrosis.
• Identified a critical role for the IL10-IL10ra axis in regulating moMac profibrotic function after injury.