The Function And Mechanism Of TMPRSS11E In Pulmonary Infectious Inflammation

In daily life,pathogens such as bacteria,fungi and viruses lead to the occurrence of acute lung injury(ALI),acute respiratory distress syndrome(ARDS)and sepsis.The outbreak of SARS-CoV-2 in recent yearshas caused great problemto public health and social economy.Although great progress has been made on the pathophysiological research of pulmonary infection and the treatment methods such as intensive care and mechanical ventilation,the molecular signaling pathways involved in the process of pulmonary infection are still unclear,and it is urgent to continuously find new targets for the treatment of pulmonary infectious diseases.In recent years,type Ⅱ transmembrane serine proteases(TTSPs)have attracted much attention because of their extensive involvement in inflammation,blood coagulation,digestion,tumor development and virus transmission.TMPRSS11E,also known as DESC1,belongs to HAT/DESC subfamily of type Ⅱ transmembrane serine protease,which is a serine protease specifically expressed in epithelial tissue.It was first found that its expression was down-regulated in head and neck squamous cell carcinoma.Currently,the research on TMPRSS11E mainly focuses on its role in the occurrence and development of tumors.In the previous research work of our laboratory,we found that TMPRSS11E was highly expressed in lung cancer tissues,and TMPRSS11E promoted the proliferation of lung cancer cells.However,whether TMPRSS11E is involved in infectious inflammation has not been reported yet.This study focuses on the function and mechanism of TMPRSS11E in infectious inflammation in the lung.In this study,for the first time,TMPRSS11E expression was found to be significantly upregulated in alveolar lavage fluid of ARDS patients.The results of in vitro experiments showed that TMPRSS11E expression was upregulated in LPS-treated lung epithelial cells,and the upregulated TMPRSS11E promoted the secretion of pro-inflammatory cytokines.By using LPS-induced acute lung injury model,CLPinduced sepsis model and poly(I:C)-induced viral infection model,in vivo results demonstrated that TMPRSS11E was induced to be up-regulated in mouse lung tissue under inflammatory pathological conditions,and we found that the up-regulated TMPRSS11E was mainly expressed in macrophages and lung epithelial cells.Overexpression of TMPRSS11E in vivo aggravated lung tissue damage and significantly reduced survival rate in CLP mice.The inflammatory response in mouse lung tissue was alleviated after TMPRSS11E knockdown.In addition,this study proved that TMPRSS11E participated in the inflammatory response by PAR1 activation.The mechanism of TMPRSS11E in pulmonary infectious inflammation was illustrated.Finally,we also found that TMPRSS11E could bind to endogenous serine protease inhibitor HAI-2.In summary,we demonstrated that TMPRSS11E was induced and up-regulated in the inflammatory pathological state,and TMPRSS11E was involved in the pulmonary infectious inflammatory response by cleaving the substrate PAR1.As a transmembrane protein,serine protease TMPRSS11E is a potential target for the treatment of lung infectious inflammatory disease.