Recognition of Bacteria by Inflammasomes

Abstract

Inflammasomes are cytosolic multiprotein complexes that assemble in response to a variety of infectious and noxious insults. Inflammasomes play a critical role in the initiation of innate immune responses, primarily by serving as platforms for the activation of inflammatory caspase proteases. One such caspase, CASPASE-1 (CASP1), initiates innate immune responses by cleaving pro-IL-1β and pro-IL-18, leading to their activation and release. CASP1 and another inflammatory caspase termed CASP11 can also initiate a rapid and inflammatory form of cell death termed pyroptosis. Several distinct inflammasomes have been described, each of which contains a unique sensor protein of the NLR (nucleotide-binding domain, leucine-rich repeat-containing) superfamily or the PYHIN (PYRIN and HIN-200 domain-containing) superfamily. Here we describe the surprisingly diverse mechanisms by which NLR/PYHIN proteins sense bacteria and initiate innate immune responses. We conclude that inflammasomes represent a highly adaptable scaffold ideally suited for detecting and initiating rapid innate responses to diverse and rapidly evolving bacteria.

Caspase‐11 activates a canonical NLRP3 inflammasome by promoting K+ efflux

“…2D). Interestingly, when analyzing the effect of MitoTEMPO on the NLRC4 inflammasome, which is directly activated by flagellin or components of type 3 secretion systems [1], we also noticed that increasing incubation times in medium containing MitoTEMPO diminished cell death and IL-1β production, indicative of off-target effects on caspase-1 activation or IL-1β secretion (Fig. 2E).…”

“…The exact cellular events involved in the activation of the NLRP3 inflammasome are still poorly understood [1]. Lysosomal damage, K + efflux, ROS, and mitochondrial DNA have been brought forward, but if and how these events are causally connected is unclear.…”

“…Inflammasomes are multiprotein complexes assembled by cytosolic PRRs from the NOD-like receptor (NLR) and PYHIN protein family upon recognition of microbe-associated molecular patterns (MAMPs) or danger signals [1]. Ligand recognition results in receptor activation and recruitment of the adaptor ASC, which rapidly oligomerizes to form the so-called ASC speck.…”

“…1C and D). In conclusion, these results argue for a model in which active caspase-11 is upstream of a canonical NLRP3 inflammasome and against the existence a noncanonical NLRP3 complex.The NLRP3 inflammasome responds to a variety of chemically and structurally diverse stimuli, among them are released danger signals such as extracellular ATP [1]. To address if caspase-11-induced host-cell lysis results in the release of cytosolic content and the activation of NLRP3 in neighboring cells, we assayed inflammasome activation in the presence of osmoprotectants.…”

GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death

“…Caspase‐1 is activated within large multi‐protein complexes termed inflammasomes, which are assembled by the protein pyrin or members of the NOD‐like receptor (NLR) and PYHIN protein families (Latz et al , 2013; von Moltke et al , 2013). These proteins act as cytosolic pattern‐recognition receptors (PRRs) and detect a variety of pathogen‐associated molecular patterns (PAMPs) or endogenous danger signals (DAMPs).…”