Dissecting The Role Of Tyrosine Phosphatase Shp2 In Macrophage-mediated Emphysema-like Injury

Pulmonary emphysema,as a major subset of chronic obstructive pulmonary disease(COPD),is characterized by excessive destruction of the alveolar wall septa,loss of lung elasticity and permanent enlargement of distal airspaces,which ultimately leads to impaired oxygenation.In recent years,emphysema is an increasing cause of morbidity and mortality worldwide with limited therapeutic options and poor prognosis due to the unknown pathogenesis.Therefore,it is of great importance to explore the pathogenesis and regulation mechanism of emphysema.During the steady state,alveolar macrophages constitute the major part of immune cells in the lungs and play essential roles in innate immune responses.Recent studies reveal that alveolar macrophages,as important endogenous sources of matrix metalloproteinases(MMPs),play central roles in the progression of emphysema.Aberrant activation of alveolar macrophages contributes to the upregulation of MMPs,which results in the degradation of extracellular matrix(ECM)and the destruction of alveolar walls.TGFβ regulates the MMP/TIMP balance and ECM homeostasis by inhibiting the expression of MMPs and promoting the expression of TIMPs.Dysregulated TGFβ signaling has been an essential determinant in the elevation of MMPs during the development of emphysema.Nevertheless,the mechanism for this TGFβ/MMP-dependent pathogenesis has not been fully studied.Reversible phosphorylation is a common modification in cell signal transduction mediated by kinase and phosphatase.Currently,protein kinase is well studied while protein phosphatase remains further investigated.Shp2 is a ubiquitously expressed non-receptor tyrosine phosphatase encoded by PTPN11 and acts as a pivotal component of diverse signaling pathways involving a variety of physiological functions.Recent study demonstrate that pharmacological inhibition of Shp2 is a valid therapeutic approach for the treatment of lung cancers.Nevertheless,the in vivo function of Shp2 in the lungs remains unclear.Our previous findings reveal that loss of Shp2 in alveoli epithelia leads to spontaneous interstitial pulmonary fibrosis.Additionally,selective disruption of Shp2 in macrophages(LysMCreShp2fl/fl)drove alternative macrophage activation.Although LysMCreShp2fl/fl mice appear to have normal lung histology at 6-8 weeks of age,fibrotic lesions in LysMCreShp2fl/fl mice are severely aggravated in a bleomycin-induced lung fibrosis model.Given that the activation of macrophages is altered due to Shp2 deficiency,we further investigated whether these Shp2 deficiency-related abnormalities cause long-term pathological outcomes in lungs.Over a long-term observation(15 months),mice with a selective deletion of Shpt in alveolar macrophages develop spontaneous emphysema-like injury in lungs,characterized by massive destruction of alveolar structure and interstitial extracellular matrix degradation.The mRNA levels of a variety of protease and anti-protease secreted by alveolar macrophages were investigated and a remarkable increase in the mRNA level of MMP-12 was found in aged LysMCreShp2fl/fl mice.Further analysis demonstrated that MMP-12 suppression by TGFβ1 activation was apparently abrogated in LysMCreShp2fl/fl mice,despite the fact that TGFβ1 concentration in the BALF was approximately the same between LysMCreShp2fl/fl mice and controls.Mechanistically,we found that loss of Shp2 resulted in attenuated SMAD2/3 phosphorylation and nuclear translocation in response to TGFβ activation,thereby up-regulating MMP-12 expression in macrophages.In addition,we found aggravated emphysema-like injury in Shp2-knockout mice in a MMP-12 dependent manner after long-term CS exposure which further verified our results of spontaneous phenotype in aged Shp2-knockout mice.In summary,our findings define a novel physiological function of Shp2 in TGFβ1/MMP-12-dependent emphysema-like injury,adding valuable insights to potential etiologies for this chronic lung disorder.