The Role Of Glutaredoxin-1 In The Regulation Of Macrophage M2 Polarization And Pulmonary Fibrosis

Idiopathic pulmonary fibrosis(IPF)is a progressive and irreversible chronic fibrosis lung disease,characterized by massive aggregation of fibroblast cells,excessive deposition of collagen,and diffuse pulmonary interstitial fibrosis remodeling,resulting in long-term gas exchange impairment and respiratory failure,and ultimately death.Patients with IPF have a short median survival and poor prognosis after diagnosis.Due to the unknown etiology and lack of effective treatment methods,it has been a hot spot and difficult point in clinical treatment and research.Macrophages are the main natural immune cells in the lung,with a high plasticity and functional diversity.Faced with different external microenvironments,macrophages can differentiate into Classically activated macrophages(M1)that promotes inflammation or Alternatively activated macrophages(M2)that inhibits inflammation and promotes tissue repair.The M2 polarization of macrophages is closely related to the process of pulmonary fibrosis.However,the specific mechanism of M2 polarization remains to be further studied.S-glutathionylation is a reversible post-translational modification process on protein active cysteine residues.It is an important regulatory mechanism of various signaling pathways and is involved in cytoskeletal assembly,cell survival and apoptosis.Deglutathionylation of proteins is regulated by glutaredoxin-1(Grx1).Grx1 is the main deglutathionylation cytoplasmic enzyme.Under physiological conditions,it can specifically break the disulfide bond between glutathione and sulfhydryl group,and it is an important way to regulate the cascade of redox signaling pathway.Protein levels and enzyme activity of Grx1 decreased in the lung tissue of IPF patients.We observed a significant reduction in Grx1 m RNA levels in fibrotic mouse lung tissues in a model of bleomycin induced pulmonary fibrosis.In vitro,we found that the absence of Grx1 enhanced the M2 activation of macrophages induced by IL4.After intraperitoneal injection of chitin,the intraperitoneal macrophages of the Grx1 knockout mice also showed stronger M2 polarization.In addition,bleomycin induced more severe pulmonary fibrosis in Grx1 KO mice than in the control group.In general,our study showed that Grx1 plays an important role in regulating macrophage polarization,and revealed that the loss of Grx1 can aggravate M2 polarization driven pulmonary fibrosis.