TGFBI Inhibits the Pyroptosis of Macrophages to Ameliorate Septic Shock

Septic shock is one of the leading causes of morbidity and mortality in hospital patients. The present study aimed to investigate the potential of transforming growth factor β induced (TGFBI) in macrophage functions and progression of septic shock. Mice were treated with caecal ligation and puncture (CLP) to establish a septic shock model in vivo. Histopathologic analysis was performed using haematoxylin and eosin (HE) staining. Gene expression was detected using reverse transcription-quantitative PCR and Western blot. Cytokine release was detected using an enzyme-linked immunosorbent assay. The enrichment of TGFBI was detected using chromatin immunoprecipitation assay. Cellular functions were detected using Cell Counting Kit-8, Lactate Dehydrogenase, flow cytometry, PI staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling staining assays. TGFBI was downregulated in septic shock patients and models. TGFBI overexpression suppressed the Pyroptosis of macrophages by inhibiting the non-canonical inflammasome, promoting the Bacterial killing ability of macrophages. Wedelolactone-mediated inhibition of Pyroptosis alleviated sepsis-induced multiple organ failure. Moreover, TGFBI inhibited M1 macrophage polarisation. Suppressor of variegation 3-9 homologue 2 (SUV39H2)-mediated histone methylation of TGFBI, resulting in the downregulation of TGFBI. Signal transducer and activator of transcription 1 (STAT1) was identified as a new co-activator of SUV39H2 to inhibit the transcription of TGFBI. However, inhibition of SUV39H2 and STAT1 upregulated TGFBI. Furthermore, STAT1 deficiency inhibited the Pyroptosis of macrophages and alleviated sepsis-induced multiple organ failure. In summary, our findings establish an immune checkpoint, whereby TGFBI, via inhibiting macrophage Pyroptosis and M1 polarisation, suppresses the progression of septic shock.

TGFBI; histone methylation; macrophage; pyroptosis; septic shock.