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

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with dismal prognosis and no cure. The potential role of the ubiquitously expressed SH2 domain-containing tyrosine phosphatase-2 (SHP2) as a therapeutic target has not been studied in IPF.Objectives: To determine the expression, mechanistic role, and potential therapeutic usefulness of SHP2 in pulmonary fibrosis.Methods: The effects of SHP2 overexpression and inhibition on fibroblast response to profibrotic stimuli were analyzed in vitro in primary human and mouse lung fibroblasts. In vivo therapeutic effects were assessed in the bleomycin model of lung fibrosis by SHP2-lentiviral administration and transgenic mice carrying a constitutively active SHP2 mutation.Measurements and Main Results: SHP2 was down-regulated in lungs and lung fibroblasts obtained from patients with IPF. Immunolocalization studies revealed that SHP2 was absent within fibroblastic foci. Loss of SHP2 expression or activity was sufficient to induce fibroblast-to-myofibroblast differentiation in primary human lung fibroblasts. Overexpression of constitutively active SHP2 reduced the responsiveness of fibroblasts to profibrotic stimuli, including significant reductions in cell survival and myofibroblast differentiation. SHP2 effects were mediated through deactivation of fibrosis-relevant tyrosine kinase and serine/threonine kinase signaling pathways. Mice carrying the Noonan syndrome-associated gain-of-function SHP2 mutation (SHP2 D61G/1 ) were resistant to bleomycin-induced pulmonary fibrosis. Restoration of SHP2 levels in vivo through lentiviral delivery blunted bleomycin-induced pulmonary fibrosis.Conclusions: Our data suggest that SHP2 is an important regulator of fibroblast differentiation, and its loss as observed in IPF facilitates profibrotic phenotypic changes. Augmentation of SHP2 activity or expression should be investigated as a novel therapeutic strategy for IPF.

PD-1 up-regulation on CD4 + T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

“…We observed PD-1 + T regs that also contain the transcription factor RORC in sarcoidosis and IPF subjects. Strikingly, PD-1 + T H 17 cells are present in pulmonary fibrosis of distinct etiologies [chronic antigenic stimulation from microbial antigens (for example, sarcoidosis) (32), genetic alterations in the Src homology 2 domain–containing phosphotyrosine phosphatase-2 (Shp2) signaling pathway (for example, IPF) (33), or bleomycin- induced pulmonary fibrosis], suggesting that the PD-1/STAT3/T H 17 pathway may represent a point of immunologic convergence resulting in organ fibrosis. The presence of PD-1 + CD4 + and CD8 + T cell up-regulation in liver and skin fibrosis has also been reported (34).…”

Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis

“…The overall prognosis of patients with IPF is highly unpredictable and poor with median survival after diagnosis being approximately 3.8 years ( 3 , 8 , 9 ). Attempts to understand disease pathogenesis, identify prognosticators, and unravel novel therapeutic targets ( 10 – 14 ) have relied on animal models. Unfortunately, no animal model fully recapitulates the histologic pattern of UIP or exhibits features of progressive disease.…”

Update in Interstitial Lung Disease 2016

“…Although the epithelium seems likely to be the site of initiation for IPF, the fibroblast and its activated form, the myofibroblast, remain the key effector cells responsible for the production of extracellular matrix in the fibrotic lung (62). With this in mind, Tzouvelekis and colleagues studied the role of H2 domain-containing tyrosine phosphatase-2 (SHP2), a ubiquitously expressed nonreceptor protein tyrosine phosphatase, in driving the profibrotic phenotype of IPF lung fibroblasts (63). In studies with IPF lung tissue, the authors found down-regulation of SHP2 within fibrotic regions.…”