Inflammasomes and the fine line between defense and disease

Abstract

Recognition of invading pathogens and execution of defensive responses are crucial steps in successfully combating infectious diseases. Inflammasomes are a group of diverse, signal-transducing complexes with key roles in both processes. While the responses mediated by inflammasomes are vital to host defense, aberrations in inflammasome regulation or activity can lead to the development of autoimmune and sterile inflammatory diseases, including cancer. The field of inflammasome research has rapidly expanded to identify novel regulatory pathways, new inflammasome components, and the mechanistic details of the activation of these complexes. In this review, we discuss recent insights into the regulation of inflammasomes by interferon regulatory factor proteins, newly discovered mechanisms of activation for the NLRP1b and NLRP6 inflammasomes, and recent studies exploring the viability of inflammasome-modulating immunotherapies.

Figure 1:

Inflammasomes can be activated through direct ligand binding or indirect mechanisms of activation. Ligand-binding activation: NAIP proteins recognize ligands from Salmonella and other bacteria to activate the NLRC4 inflammasome. AIM2 binds to cytosolic DNA freed by GBP and IRG proteins to assemble the AIM2 inflammasome and initiate pyroptosis. The NLRP6 inflammasome is activated by cytosolic LTA from Gram-positive bacteria, including L. monocytogenes, to cleave CASP11 and CASP1, though CASP1 does not appear to cleave GSDMD when activated by NLRP6. Indirect activation: The FIIND domain of NLRP1B undergoes autoproteolysis but stays associated with the C-terminus of the protein. Anthrax protective antigen and lethal factor (PA/LF) lead to N-terminal NLRP1B cleavage, targeting it for ubiquitination and degradation and allowing the C-terminus to activate the inflammasome. The pyrin inflammasome becomes active after Rho GTPase inactivation by toxins. NLRP3 is activated through a variety of mechanisms. dsDNA, double-stranded DNA; LRR, leucine-rich repeat; nGSDMD, N-terminal region of gasdermin D; NOD, nucleotide oligomerization domain.