Irgm2 and Gate-16 cooperatively dampen targeting of caspase-11 to Gram-negative bacterial products

Abstract

27Inflammatory caspase-11 (rodent) and caspases-4 and -5 (human) detect gram-28 negative bacterial component LPS in the host cell cytosol, which promotes activation 29 of the non-canonical inflammasome. Although non-canonical inflammasome-induced 30 pyroptosis and IL-1 related cytokine release is of importance to mount an efficient 31 immune response against various bacteria, its unrestrained activation drives sepsis. 32 This suggests that cellular components might tightly control the threshold level of the 33 non-canonical inflammasome in order to ensure efficient but not deleterious 34 inflammatory response. Here we show that the IFN-inducible protein Irgm2 and the 35 ATG8 family member Gate-16 cooperatively slow down non-canonical inflammasome 36 activation both in macrophages and in vivo. Specifically, the Irgm2/Gate-16 axis 37 dampens caspase-11 targeting to intracellular bacteria, which lower caspase-11-38 mediated pyroptosis and cytokine release. Specifically, deficiency in Irgm2 or Gate16 39 opens an alternative road for caspase-11 targeting to intracellular bacteria, 40 independently of the classical pathway driven by the Guanylate Binding Proteins 41 (GBPs). Thus, our findings provide new molecular effectors involved at fine-tuning the 42 optimal non-canonical inflammasome response and add novel insights in the 43 understanding of the immune pathways they control.44 45

Outer membrane vesicles produced by pathogenic strains of Escherichia coli block autophagic flux and exacerbate inflammasome activation

“…Thus, this inflammation machinery initiated by OMV recognition must be tightly regulated. Here, we show that OMV HlyF WT provoke an exacerbated activation of the non-canonical inflammasome activation and IL-1β release, one of the main mechanisms through which innate and adaptive immune responses are induced by an infection (Eren et al, 2020;Gomes and Dikic, 2014;Schroder et al, 2018). We showed that not only OMVs HlyF WT induces inflammation actions, they also block autophagy, a major negative regular of excessive inflammation activation and IL-1β release (Crişan et al, 2011;Saitoh et al, 2008).…”

“…It is then followed by an immunosuppression due to the massive apoptosis of macrophages, which makes host susceptible to recurrent infections (Cecconi et al, 2018;van der Poll et al, 2017). The role of OMVs in sepsis is highlighted by the fact that injection of OMVs alone in mice recapitulates sepsis-associated exacerbated inflammation and mortality (Eren et al, 2020). Thus, this inflammation machinery initiated by OMV recognition must be tightly regulated.…”

Outer membrane vesicles produced by pathogenic strains of Escherichia coli block autophagic flux and exacerbate inflammasome activation

“…Thus, this inflammation machinery initiated by OMV recognition must be tightly regulated. Here we show that OMV HlyF WT provoke an exacerbated activation of the non-canonical inflammasome activation and IL-1β release, one of the main mechanisms through which innate and adaptive immune responses are induced by an infection (Eren et al, 2020; Gomes and Dikic, 2014; Schroder et al, 2018). We showed that not only OMVs HlyF WT induces inflammation actions via LPS presentation, they also block autophagy, a major negative regular of excessive inflammation activation and IL-1β release (Crişan et al, 2011; Saitoh et al, 2008).…”

“…It is then followed by an immunosuppression due to the excessive apoptosis of macrophages, which makes host susceptible to recurrent infections (Cecconi et al, 2018; van der Poll et al, 2017). The role of OMVs in sepsis is highlighted by the fact that injection of OMVs alone in mice recapitulates sepsis-associated exacerbated inflammation and mortality (Eren et al, 2020). Thus, this inflammation machinery initiated by OMV recognition must be tightly regulated.…”

“…The role of OMVs in sepsis is highlighted by the fact that injection of OMVs alone in mice recapitulates sepsis-associated exacerbated inflammation and mortality (Eren et al, 2020). Thus, this inflammation machinery initiated by OMV recognition must be tightly regulated.…”