Paired immunoglobulin-like receptor-B inhibits pulmonary fibrosis by suppressing profibrogenic properties of alveolar macrophages.

Rationale: Macrophages are lung-resident cells that play key roles in fibrosis. Surprisingly, pathways that inhibit macrophage functions, especially in idiopathic pulmonary fibrosis (IPF), received little attention. The cell-surface molecule paired immunoglobulin-like receptor B (PIR-B) can suppress macrophage activation. Yet, its role in pulmonary fibrosis is unknown. Objective: To define the role of PIR-B in IPF. Methods: The expression of PIR-B was assessed (qPCR, flow cytometry) following bleomycin treatment. Differential cell counts, histopathology and profibrogenic-mediator expression (e.g. Collagen, α-SMA, Relm-α, MMP-12, TIMP-1) were determined (ELISA, qPCR, flow cytometry) in the lungs of wild type and Pirb-/- mice following bleomycin or IL-4 treatment. Bone marrow-derived wild-type and Pirb-/- macrophages were stimulated with IL-4 and assessed for Relm-α and MMP-12 expression. Measurements and Main Results: PIR-B was upregulated in lung myeloid cells following bleomycin administration. Bleomycin-treated Pirb-/- mice displayed increased lung histopathology, increased collagen expression and of the IL-4-associated profibrogenic markers Relm-α, MMP-12, TIMP-1 and osteopontin, which were localized to alveolar macrophages. Increased profibrogenic mediator expression in Pirb-/- mice was not due to increased IL-4/IL-13 levels, suggesting that PIR-B negatively regulates IL-4-induced macrophage activation. Indeed, IL-4 treated Pirb-/- mice displayed increased Relm-α expression and Relm-α+ macrophage levels. IL-4-activated Pirb-/- macrophages displayed increased Relm-α and MMP-12 induction. Finally, LILRB3/ILT-5, the human PIR-B ortholog was expressed and upregulated in lung biopsies from IPF patients. Conclusions: Our results establish a key role for PIR-B in IPF, likely via regulation of macrophage activation. Therefore, PIR-B/LILRB3 may be a possible target for suppressing macrophage profibrogenic activity in IPF