Noncanonical Inflammasome Activation by Intracellular LPS Independent of TLR4

Abstract

Gram-negative bacteria including Escherichia coli, Citrobacter rodentium, Salmonella typhimurium, and Shigella flexneri are sensed in an ill-defined manner by an intracellular inflammasome complex that activates caspase-11. We show that macrophages loaded with synthetic lipid A, E. coli lipopolysaccharide (LPS), or S. typhimurium LPS activate caspase-11 independently of the LPS receptor Toll-like receptor 4 (TLR4). Consistent with lipid A triggering the noncanonical inflammasome, LPS containing a divergent lipid A structure antagonized caspase-11 activation in response to E. coli LPS or Gram-negative bacteria. Moreover, LPS-mutant E. coli failed to activate caspase-11. Tlr4(-/-) mice primed with TLR3 agonist polyinosinic:polycytidylic acid [poly(I:C)] to induce pro-caspase-11 expression were as susceptible as wild-type mice were to sepsis induced by E. coli LPS. These data unveil a TLR4-independent mechanism for innate immune recognition of LPS.

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…In a TLR4-independent manner, endocytosed LPS activates caspase-11 and stimulates the production of IL-1b/IL-18 (Fig. 3) (Kayagaki et al 2013). In addition, another group has shown that cytosolic LPS activates caspase-11, resulting in endotoxic shock in mice (Hagar et al 2013).…”

Burn the house, save the day: pyroptosis in pathogen restriction

“…Although seemingly intended as a mechanism to prevent infection of daughter cells from compromised haematopoietic progenitor cells, chronic pyroptosis resulted in cytopenia and immunosuppression [46,47]. Lastly, caspase-11-mediated pyroptosis may drive lethal endotoxemia by mediating the release of intracellular inflammatory mediators [17,18,48]. Collectively, such observations highlight the potential for pyroptosis to mediate pathology under certain conditions.…”

“…The inflammatory caspase sub-family is comprised of caspases-1, -4, -5, and -12 in humans and -1, -11, and -12 in mice. Caspase-11 has gained considerable attention in recent years, as it is activated upon intracellular delivery of bacterial lipopolysaccharide (LPS), and is implicated into endotoxemia [17,18]. Like caspase-1, active caspase-11 triggers pyroptosis.…”

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

“…This noncanonical inflammasome induces GSDMD-mediated cell death and IL-1␣ secretion independently of caspase-1 in response to caspase-11-mediated sensing of cytosolic LPS (14,15,(19)(20)(21). Caspase-11-dependent cleavage of GSDMD and subsequent pore formation also triggers activation of the canonical NLRP3 inflammasome by inducing potassium efflux (22)(23)(24).…”