title: Myeloid-specific disruption of tyrosine phosphatase Shp2 promotes alternative activation of macrophages and predisposes mice to pulmonary fibrosis.
abstract: The alternative activation of M2 macrophages in the lungs has been implicated as a causative agent in pulmonary fibrosis; however, the mechanisms underlying M2 polarization are poorly characterized. In this study, we investigated the role of the ubiquitously expressed Src homology domain-containing tyrosine phosphatase Shp2 in this process. Shp2 inactivation augmented IL-4-mediated M2 polarization in vitro, suggesting that Shp2 regulates macrophage skewing and prevents a bias toward the M2 phenotype. Conditional removal of Shp2 in monocytes/macrophages with lysozyme M promoter-driven Cre recombinase caused an IL-4-mediated shift toward M2 polarization. Additionally, an increase in arginase activity was detected in Shp2(∆/∆) mice after i.p. injection of chitin, whereas Shp2-deficient macrophages showed enhanced M2 polarization and protection against schistosome egg-induced schistosomiasis. Furthermore, mutants were more sensitive than control mice to bleomycin-induced inflammation and pulmonary fibrosis. Shp2 was associated with IL-4Rα and inhibited JAK1/STAT6 signaling through its phosphatase activity; loss of Shp2 promoted the association of JAK1 with IL-4Rα, which enhanced IL-4-mediated JAK1/STAT6 activation that resulted in M2 skewing. Taken together, these findings define a role for Shp2 in alveolar macrophages and reveal that Shp2 is required to inhibit the progression of M2-associated pulmonary fibrosis.
authors.affiliation: Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tao
authors.affiliation: Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.affiliation: Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; and.
authors.forename: Zuyu
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; and.
authors.forename: Junlin
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; and.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China.
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China yke@zju.edu.cn.
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Ke
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D001761:Bleomycin / Q000009:adverse effects / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D002686:Chitin / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced; D018793:Interleukin-13 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D015848:Interleukin-5 / Q000096:biosynthesis; D053613:Janus Kinase 1 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000276:immunology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface / Q000276:immunology; D050800:STAT6 Transcription Factor / Q000096:biosynthesis; D012549:Schistosoma japonicum / Q000276:immunology*; D012554:Schistosomiasis japonica / Q000276:immunology* / Q000469:parasitology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D001119:Arginase; D001761:Bleomycin; D002686:Chitin; D018793:Interleukin-13; D015847:Interleukin-4; D015848:Interleukin-5; D053613:Janus Kinase 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C494100:Stat6 protein, mouse; C507905:Jak1 protein, mouse; C516725:Ptpn11 protein, mouse