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.

SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis

“…We hypothesize that SHP2 overexpression or inhibition promotes significant alterations in the phosphorylation states of several proteins involved in major signal transduction pathways. Because of the ubiquitous expression of SHP2 and its multitude of effects, it is possible that SHP2 inhibition may alter the general phosphorylation/dephosphorylation state of multiple signal transduction pathways in other cell types, not only fibroblasts, thus making the lung, as an organ, more susceptible to fibrosis, as has been previously described (19,20). This does not reduce the significant value of our observation that overexpression of catalytically active SHP2 has the potential to blunt fibrosis.…”

“…Global SHP2 deficiency is embryonically lethal in mice, due to major developmental defects (33,36). Support for a potential role for SHP2 in lung fibrosis has emerged from observations that targeted genetic ablations of SHP2 in AECs (19) or macrophages (20) are profibrotic. However, these studies did not assess the expression of SHP2 in human pulmonary fibrosis.…”

“…SHP2 regulates activated tyrosine kinase receptors including PDGFR, by binding to and dephosphorylating them (17,18). In mice targeted deletions of SHP2 in alveolar epithelial cells (AECs) (19) or macrophages (20) increase predisposition to fibrosis, but the expression of SHP2 in human pulmonary fibrosis or its potential therapeutic usefulness are still unknown.…”

Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

“…M2 macrophage activation has been implicated in the development of pulmonary fibrosis (61)(62)(63) (Figures 2E, F). This finding indicates that inflammation was equivalent in BLM-challenged wild-type and α7 nAChR knockout mice, which could explain why deficiency of α7 nAChR did not affect BAL protein levels, an index of lung epithelial and endothelial permeability ( Figure 1).…”

Taking It Off: New Insights into the Role of Tyrosine Phosphorylation–dependent Pathways in the Pathogenesis of Pulmonary Fibrosis

“…Compared with protein tyrosine kinases, much less is known about the role of PTPs in fibrogenesis. Genetic deletion of SHP2 in alveolar epithelial cells results in spontaneous pulmonary fibrosis in mice, possibly related to dysregulated surfactant homeostasis (10); similarly, genetic deletion of SHP2 in macrophages enhanced bleomycin-induced pulmonary fibrosis in mice, possibly by M2-skewing of the pulmonary inflammatory response (11). We have reported that mice genetically deficient in PTPa are protected from experimental pulmonary fibrosis (12).…”