| First Author | Tao B | Year | 2014 |
| Journal | J Immunol | Volume | 193 |
| Issue | 6 | Pages | 2801-11 |
| PubMed ID | 25127857 | Mgi Jnum | J:234895 |
| Mgi Id | MGI:5791054 | Doi | 10.4049/jimmunol.1303463 |
| Citation | Tao B, et al. (2014) Myeloid-specific disruption of tyrosine phosphatase Shp2 promotes alternative activation of macrophages and predisposes mice to pulmonary fibrosis. J Immunol 193(6):2801-11 |
| abstractText | 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-4Ralpha and inhibited JAK1/STAT6 signaling through its phosphatase activity; loss of Shp2 promoted the association of JAK1 with IL-4Ralpha, 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. |
