Abstract
The NLRP3 inflammasome is a multi-protein complex that initiates innate immunity responses when exposed to a wide range of stimuli, including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Inflammasome activation leads to the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and to pyroptotic cell death. Over-activation of NLRP3 inflammasome has been associated with several chronic inflammatory diseases. A deep knowledge of NLRP3 inflammasome biology is required to better exploit its potential as therapeutic target and for the development of new selective drugs. To this purpose, in the past few years, several tools have been developed for the biological characterization of the multimeric inflammasome complex, the identification of the upstream signaling cascade leading to inflammasome activation, and the downstream effects triggered by NLRP3 activation. In this review, we will report cellular models and cellular, biochemical, and biophysical assays that are currently available for studying inflammasome biology. A special focus will be on those models/assays that have been used to identify NLRP3 inhibitors and their mechanism of action.
Highlights
Innate immunity represents the first line of defense against invading pathogens or endogenous stress signals
The inflammatory cascade is triggered by the recognition of pathogen-associated molecular pattern (PAMP) and danger-associated molecular pattern (DAMP) by pattern recognition receptors (PRRs) that are mainly expressed by immune cells, such as macrophages
Inflammasome assembly occurs upon activation of the TLR4 by LPS triggering the TIR-domain-containing adapter-inducing interferon-β (TRIF)—receptor-interacting serine/threonine-protein kinase 1 (RIPK1)—Fas-associated protein with death domain (FADD) caspase-8 signaling cascade, which in turns leads to the activation of the NLRP3 inflammasome
Summary
Innate immunity represents the first line of defense against invading pathogens or endogenous stress signals. It exists in human and porcine peripheral blood mononuclear cells (PBMCs), but it is absent in murine ones [32] In this pathway, LPS per se is sufficient to induce activation of the NLRP3 inflammasome with consequent activation of caspase-1 and IL-1β processing and secretion. Inflammasome assembly occurs upon activation of the TLR4 by LPS triggering the TIR-domain-containing adapter-inducing interferon-β (TRIF)—receptor-interacting serine/threonine-protein kinase 1 (RIPK1)—Fas-associated protein with death domain (FADD) caspase-8 signaling cascade, which in turns leads to the activation of the NLRP3 inflammasome. This pathway is not dependent on K+ efflux. IL-1β is released gradually, as opposed to the all-or-nothing response of the canonical activation [32]
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