From Gene to Intervention: NLRC4 and WIPI1 Regulate Septic Acute Lung Injury Through Autophagy.

Abstract

Background: Septic Acute Lung Injury (SALI)-induced severe respiratory dysfunction has been established to significantly increase patient mortality rates and socioeconomic costs. To mitigate cellular damage, autophagy -a conserved biological process in organisms -degrades damaged cellular components, such as proteins and organelles. Although autophagy is crucially involved in the inflammatory response, its precise molecular mechanisms in SALI remain unclear, forming the basis of this study.

Methods: Herein, two microarray datasets (GSE33118 and GSE131761) and three single-cell sequencing datasets (SCP43, SCP548, and SCP2156) derived from human samples were used to ascertain the interrelationship between Differentially Expressed Autophagy-Related Genes (DEARGs) and SALI. The relationship between key DEARGs and SALI was validated both in vitro and in vivo using various techniques, including flow cytometry, Immunofluorescence (IF), Quantitative Polymerase Chain Reaction (qPCR), Western Blotting (WB), and small interfering RNA (siRNA).

Results: Herein, we found that autophagy activation attenuated SALI, with NLRC4 and WIPI1 as the two key DEARGs involved. Specifically, NLRC4 and WIPI1 downregulation mitigated SALI via autophagy activation. Compared to NLRC4, WIPI1 was more closely associated with noncanonical autophagic flux in SALI. Furthermore, immune infiltration analysis and single-cell data showed a close relationship between NLRC4, WIPI1, and immune cells.

Conclusion: Our findings revealed that SALI correlated strongly with autophagy, with the downregulation of the two key DEARGs, NLRC4 and WIPI1, attenuating sepsis lung injury via autophagy regulation, highlighting their therapeutic significance in SALI.