Mechanisms of inflammasome activation: recent advances and novel insights

Abstract

Inflammasomes are cytosolic multiprotein platforms assembled in response to invading pathogens and other danger signals. Typically inflammasome complexes contain a sensor protein, an adaptor protein, and a zymogen - procaspase-1. Formation of inflammasome assembly results in processing of inactive procaspase-1 into an active cysteine-protease enzyme, caspase-1, which subsequently activates the proinflammatory cytokines, interleukins IL-1β and IL-18, and induces pyroptosis, a highly-pyrogenic inflammatory form of cell death. Studies over the past year have unveiled exciting new players and regulatory pathways that are involved in traditional inflammasome signaling, some of them even challenging the existing dogma. This review outlines these new insights in inflammasome research and discusses areas that warrant further exploration.

Keywords: ALRs; NLRs; caspase-11; inflammasomes; non-canonical inflammasome.

Figure 1. Canonical inflammasomes

Canonical inflammasomes contain sensors belonging to the NLR or ALR family. NLRC4 is activated by bacterial flagellin and T3SS components, NLRP1b is activated by anthrax lethal toxin and AIM2 is activated by cytosolic dsDNA. NLRP3 is activated by a wide variety of signals including pore-forming cytotoxins, ATP, uric acid and alum. Once activated the receptors form an inflammasome complex with or without the adaptor, ASC, and recruits procaspase-1, which is subsequently cleaved into active caspase-1. Caspase-1 cleaves preforms of IL-1β and IL-18 into their active forms as well as induces cell death.

Figure 2. Pyrin and NLRP6: newly characterized inflammasomes with atypical activators and downstream effects

Unlike classical inflammasomes Pyrin senses pathogen-induced alterations in cellular machinery such as modifications in Rho GTPases. The activator of NLRP6 is not yet identified. In addition to inducing caspase-1 activation and subsequent IL-1 cytokine production, NLRP6 inflammasome sustains intestinal homeostasis. NLRP6 regulates autophagosome formation, which is essential for mucin granule exocytsosis from goblet cells and maintenance of intestinal barrier integrity.

Figure 3. Non-canonical inflammasome activation by cytosolic LPS

Gram-negative bacterial infections lead to the activation of TLR4-TRIF-type I IFN pathway as well as assembly of NLRP3 inflammasome. Type I IFN induces the expression caspase-11. Caspase-11 oligomerizes upon binding with cytosolic LPS from bacteria and this active caspase-11 controls NLRP3 inflammasome-dependent cleavage of caspase-1 through an unknown mechanism.