Contribution Of Progranulin To Protective Lung Immunity During Bacterial Pneumonia

Objective:Lower respiratory tract infection is associated with highest morbidity rates of any diseases worldwide,which has been the fourth most common cause of death,only followed by cardiovascular and cerebrovascular disease,COPD.Bacteria are the most frequent cause of community-acquired pneumonia.Pulmonary immunity plays a central role in the defense against microbes in the lung,where a variety of inflammatory mediators,including cytokines,chemokines,and growth factors regulate infection and immunity.Precious studies showed that progranulin?PGRN?is an autocrine growth factor involved in a variety of inflammatory diseases.However,its role in pulmonary immunity against bacterial infection remains unknown.Here we investigate the effect of progranulin during bacterial pneumonia and further explore the underlying immunomodulatory mechanism,which provides more and novel experimental evidences for the study of molecular mechanism in bacterial pneumonia.Methods:Patients with community-acquired pneumonia were recruited from Children's Hospital of Chongqing Medical University.Then the amount of PGRN in clinical samples from patients and healthy control is determined by ELISA.After establishing the pneumonia model of mice infected with S.aureus 502A or P.aeruginosa PAK,which mimics the natural route of infection during human pneumonia,PGRN content is assayed by ELISA.Next,in the vivo experiment,by the monitor of mice survival and the severity of clinical symptoms during pneumonia,the potential role of PGRN in pulmonary infection is evaluated.Meanwhile,the impaired host defense in PGRN^-/-mice is assayed by the bacterial burden and pulmonary pathological injury.Expression of cytokines and chemokines in infected sites are tested by ELISA assay.The percentage and absolute number of macrophages and neutrophils are both detected by FCM.Lastly,the administration of exogenous recombinant progranulin at 2 hours after infection can be used to assess the therapeutic effects of PGRN on bacterial pneumonia.Results:Patients with community-acquired pneumonia displayed elevated PGRN levels.Likewise,mice with Gram-negative and Gram-positive pneumonia had increased PGRN production in the lung and circulation.Progranulin deficiency led to increased bacterial growth and dissemination accompanied by enhanced lung injury and mortality in bacterial pneumonia,which was associated with impaired recruitment of macrophages and neutrophils in the lung.The reduced number of pulmonary macrophages and neutrophils observed in PGRN-deficient mice was related to a reduction of CCL2 and CXCL1 in the lungs after bacterial pneumonia.Importantly,therapeutic administration of PGRN improved mortality in severe bacterial pneumonia,as reflected by the increased survival and bacterial clearance.Conclusions:This study supports a novel role for PGRN in pulmonary immunity and suggests that treatment with PGRN may be a viable therapy for bacterial pneumonia.