Inflammatory caspases are innate immune receptors for intracellular LPS

Abstract

The murine caspase-11 non-canonical inflammasome responds to various bacterial infections. Caspase-11 activation-induced pyroptosis, in response to cytoplasmic lipopolysaccharide (LPS), is critical for endotoxic shock in mice. The mechanism underlying cytosolic LPS sensing and the responsible pattern recognition receptor are unknown. Here we show that human monocytes, epithelial cells and keratinocytes undergo necrosis upon cytoplasmic delivery of LPS. LPS-induced cytotoxicity was mediated by human caspase-4 that could functionally complement murine caspase-11. Human caspase-4 and the mouse homologue caspase-11 (hereafter referred to as caspase-4/11) and also human caspase-5, directly bound to LPS and lipid A with high specificity and affinity. LPS associated with endogenous caspase-11 in pyroptotic cells. Insect-cell purified caspase-4/11 underwent oligomerization upon LPS binding, resulting in activation of the caspases. Underacylated lipid IVa and lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) could bind to caspase-4/11 but failed to induce their oligomerization and activation. LPS binding was mediated by the CARD domain of the caspase. Binding-deficient CARD-domain point mutants did not respond to LPS with oligomerization or activation and failed to induce pyroptosis upon LPS electroporation or bacterial infections. The function of caspase-4/5/11 represents a new mode of pattern recognition in immunity and also an unprecedented means of caspase activation.

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

“…Basal expression of CASP4 is low in resting cells and its expression and activity are triggered by bacterial factors such as intracellular lipopolysaccharide [27,28]. To determine if B. cenocepacia infection of WT macrophages induces CASP4 protein expression, macrophages were infected with bacteria for 2 h or 6 h and the expression of CASP4 was evaluated by immunoblot.…”

Old, new and emerging functions of caspases

“…This represents a novel mechanism for inflammasome activation that is distinct from LPS sensing and activation of caspase-1. 58 In contrast to the roles of other inflammatory cytokines, caspase-12 can abrogate the inflammatory response in mice by inhibiting caspase-1, in a protease-independent function. 59 As a result, mice deficient for caspase-12 show increased bacterial clearance and resistance to sepsis.…”

GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death

“…Initial work has identified the pro‐inflammatory cytokine interleukin (IL)‐1β as a key substrate of caspase‐1 (Thornberry et al , 1992). Subsequently, it was found that caspase‐1, as well as caspase‐11 and its human orthologs caspase‐4 and caspase‐5, induces a novel programmed cell death pathway that is characterized by cell swelling, lysis, and the release of cytoplasmic content (Fink & Cookson, 2007; Kayagaki et al , 2011; Shi et al , 2014), presumably as a result of the formation of membrane pores (Fink et al , 2008). Since this type of cell death is morphologically distinct from apoptosis and intrinsically pro‐inflammatory, it was named pyroptosis, from the Greek pyro (fire or fever) and ptosis (to fall) (Bergsbaken et al , 2009).…”