What do we know about the inflammasome in humans?

Abstract

The inflammasome complex is part of the innate immune system, which serves to protect the host against harm from pathogens and damaged cells. It is a term first proposed by Tschopp's group in 2002, with numerous original research articles and reviews published on the topic since. There have been many types of inflammasome identified, but all result in the common pathway of activation of caspases and interleukin 1β along with possible cell death called pyroptosis. Despite a growing body of research investigating the structure and function of the inflammasome in animal models, there is still limited evidence identifying inflammasome components in human physiology and disease. In this review, we explore the molecular structure and mechanism of activation of the inflammasome with a particular focus on inflammasome complexes expressed in humans. Inflammasome components have been identified in several human peripheral and brain tissues using both in vivo and ex vivo work, and the inflammasome complex has been shown to be associated with several genetic and acquired inflammatory and neoplastic disorders. We discuss the strengths and weaknesses of the information available on the inflammasome with an emphasis on the importance of prioritizing work on human tissue. There is a huge demand for more effective treatments for a number of inflammatory and neurodegenerative diseases. Modulation of the inflammasome has been proposed as a novel treatment for several of these diseases and there are currently clinical trials ongoing to test this theory.

Keywords: NLRP; human; inflammasome; inflammasomopathies; inflammation; innate immunity.

Figure 1

Schematic illustration of the inflammasome complex. (A) The different steps involved in inflammasome formation. Three main components of the inflammasome (sensor, adaptor and caspase) are shown in the yellow rectangle. Some PRRs, such as NLRP1, can bind caspase directly (large, curvy arrow), without need of the adaptor. (B) The members of PRR superfamily as part of the inflammasome complex: directly (canonical) or indirectly (non‐canonical). (C) The inflammasome pathways: canonical directly initiates caspase 1 activation, and non‐canonical uses other caspases to facilitate inflammation.

Figure 2

Schematic representation of the two pathways and components involved in inflammasome activation. (A) The canonical pathway. Upon inflammasome formation, caspase 1 (red) directly activates cytokines IL1β, IL18 and pyroptotic gasdermin D. (B) The non‐canonical pathways. (i) LPS can activate caspase 4/5 (blue) directly (large, curvy arrow) or via the TLR4 receptor, leading to gasdermin D maturation and pyroptosis. Cleaved Gasdermin D may then activate the NLRP3 inflammasome. (ii) Various pathogen signals (PAMPs), via CTL receptor, may initiate formation of the caspase 8 inflammasome (green). The product of both non‐canonical inflammasomes is IL1β.