SerpinE3 is a novel endogenous regulator of inflammation via TMPRSS11E inhibition

Although SerpinE3, an extracellular serine protease inhibitor, has been documented in several studies, its biological function remains largely undefined. In a screen for interactors of TMPRSS11E-a protease known to exacerbate inflammation and lung injury during infection-we identified a novel interaction with SerpinE3. Initially, we assessed the inhibitory effect of SerpinE3 on TMPRSS11E activity using synthetic fluorescent substrates PAR1 and PAR2 peptides. We further characterized SerpinE3 expression patterns in mouse cecal ligation and puncture (CLP) models of inflammation and in patients with pneumonia. Subsequently, the anti-inflammatory effects of SerpinE3 were investigated in both in vitro and in vivo inflammatory models. Finally, we examined the regulatory mechanisms governing SerpinE3 expression via promoter activity assays and electrophoretic mobility shift assays (EMSA). Our results demonstrate that SerpinE3 directly inhibits TMPRSS11E activity. SerpinE3 expression was significantly upregulated in alveolar and liver macrophages under inflammatory conditions. Administration of recombinant SerpinE3 protein markedly alleviated inflammation and acute lung injury in the mouse CLP model. Conversely, SerpinE3 knockout mice exhibited aggravated lung injury, a phenotype that was rescued by recombinant protein administration. Notably, aged SerpinE3 knockout mice displayed a spontaneous accumulation of inflammatory cells in the lungs. Mechanistically, we identified a functional NF-κB response element within the proximal promoter of SerpinE3. In conclusion, we identify SerpinE3 as an infection-inducible, macrophage-derived regulator that attenuates inflammatory lung injury, likely through the inhibition of TMPRSS11E. This study elucidates a critical anti-inflammatory role for SerpinE3 and paves the way for developing SerpinE3-based therapies for inflammatory acute lung injury.