Polymeric Immunoglobulin Receptor Promotes Lung Injury In Sepsis Through Caspase-11 Mediated Pyroptosis

Background:In the definition of sepsis 3.0,sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.It has been reported that in 2017,there were about 48.6 million sepsis patients worldwide,and the death toll reached as high as 11 million,accounting for 19.7%of the total annual death toll in the world^[1].Therefore,sepsis is a major threat to human health and social and economic development,and its pathogenesis and lethal mechanism are currently a major medical problem.Polymeric immunoglobulin receptor（pIgR）can transport Polymeric Immunoglobulins （p Igs）through the lamina propria and across the epithelial barrier to the mucosal surface,forming a defense mechanism of pIgR/Secretory Immunoglobulins（s Igs）,which plays an important role in the mucosal system.It has been reported that in patients with chronic obstructive pneumonia,the plasma pIgR level is significantly increased^[2].However,there is no report on the role of plasma pIgR in sepsis.In the previous study,we found that the content of plasma pIgR increased in Pneumonia Induce Sepsis（PIS）,and intravenous injection of pIgR decreased the survival rate of mice in Klebsiella pneumoniae sepsis（KPS）model.Therefore,based on the previous study,this study further explored the mechanism of plasma pIgR in sepsis.Methods:We selected plasma samples from healthy people,patients with Digestive infection without sepsis（DI）and patients with digestive infection-induced sepsis（DIS）from the septic biological sample bank and detected the concentration of pIgR in the plasma samples by ELISA to determine the correlation between the level of plasma pIgR and sepsis.To investigate the role of plasma pIgR in sepsis and its underlying mechanisms,KPS mice were intravenously injected with recombinant mouse pIgR and pIgR antibodies,and the lung tissues were evaluated for histopathological changes using H&E staining,as well as for caspase-11 and GSDMD proteins in lung tissues using protein blot and immunostaining.In addition,we evaluated the effect of pIgR on the release of IL-1βfrom primary bone marrow macrophages（BMDM）.Results:1.Plasma pIgR concentrations in patients with DIS were not affected by age and gender,but were significantly higher than those in the healthy population and patients with DI.2.The recombinant mouse pIgR aggravates the damage and inflammatory cell infiltration in the lung tissue of KPS mice,and increases the level of Pro-caspase-11,as well as the hydrolysis and activation of caspase-11 and GSDMD in the lung tissue.3.pIgR antibody increases the survival rate of KPS mice,reduces the damage to lung tissue,reduces the level of Pro-caspase-11 in lung tissue,as well as the hydrolysis and activation of caspase-11 and GSDMD.Conclusion:Elevated plasma pIgR may be a common manifestation of sepsis.Plasma pIgR promotes septic lung injury through caspase-11-mediated pyroptosis.