title: Paired immunoglobulin-like receptor-B inhibits pulmonary fibrosis by suppressing profibrogenic properties of alveolar macrophages.
abstract: Macrophages are lung-resident cells that play key roles in fibrosis. Surprisingly, pathways that inhibit macrophage functions, especially in idiopathic pulmonary fibrosis (IPF), receive little attention. The cell-surface molecule paired immunoglobulin-like receptor B (PIR-B) can suppress macrophage activation. However, its role in pulmonary fibrosis remains unknown. We sought to define the role of PIR-B in IPF. The expression of PIR-B was assessed (by quantitative PCR and flow cytometry) after bleomycin treatment. Differential cell counts, histopathology, and profibrogenic-mediator expression, for example, collagen, α-smooth muscle actin, resistin-like molecule-α (Relm-α), matrix metalloproteinase (MMP)-12, and tissue inhibitor of metalloproteinase (TIMP)-1, were determined (by ELISA quantitative PCR and flow cytometry) in the lungs of wild-type and Pirb(-/-) mice after 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. PIR-B was up-regulated in lung myeloid cells after bleomycin administration. Bleomycin-treated Pirb(-/-) mice displayed increased lung histopathology and an increased expression of collagen 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 attributable to increased IL-4/IL-13 concentrations, 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 concentrations. IL-4-activated Pirb(-/-) macrophages displayed increased Relm-α and MMP-12 induction. Finally, leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3)/immunoglobulin-like transcript-5, the human PIR-B orthologue, was expressed and up-regulated in lung biopsies from patients with IPF. Our results establish a key role for PIR-B in IPF, likely via the regulation of macrophage activation. Therefore, PIR-B/LILRB3 may offer a possible target for suppressing macrophage profibrogenic activity in IPF.
authors.affiliation: Department of Microbiology and Clinical Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
authors.forename: Danielle
authors.initials: D
authors.lastname: Karo-Atar
authors.forename: Itay
authors.initials: I
authors.lastname: Moshkovits
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.forename: Ariel
authors.initials: A
authors.lastname: Munitz
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D036341:Intercellular Signaling Peptides and Proteins; C105949:Pirb protein, mouse; D011971:Receptors, Immunologic; C413576:Retnla protein, mouse; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D001761:Bleomycin; D015847:Interleukin-4; D053508:Matrix Metalloproteinase 12