Post-phagocytosis activation of NLRP3 inflammasome by two novel T6SS effectors.

The type VI secretion system (T6SS) is used by bacteria to deliver toxic effectors directly into target cells. Most T6SSs mediate antibacterial activities, whereas the potential anti-eukaryotic role of T6SS remains understudied. Here, we found a T6SS that delivers two novel effectors into mammalian host immune cells.

pore-forming leukocidin activates pyroptotic cell death via the NLRP3 inflammasome.

Cell death mechanisms are central to combat infections and to drive inflammation. The inflammasome controls infection through activation of caspase-1 leading to either IL-1β dependent inflammation, or pyroptotic cell death in infected cells. Hemolysins, which are pore-forming toxins (PFTs), alter the permeability of the host target membrane, often leading to cell death.

Necroptosis directly induces the release of full-length biologically active IL-33 in vitro and in an inflammatory disease model.

Interleukin-33 (IL-33) is a pro-inflammatory cytokine that plays a significant role in inflammatory diseases by activating immune cells to induce type 2 immune responses upon its release. Although IL-33 is known to be released during tissue damage, its exact release mechanism is not yet fully understood. Previously, we have shown that cleaved IL-33 can be detected in the plasma and epithelium of Ripk1 neonates, which succumb to systemic inflammation driven by spontaneous receptor-interacting protein kinase-3 (RIPK3)-dependent necroptotic cell death, shortly after birth.