Inflammasome: structure, biological functions, and therapeutic targets

Abstract

Inflammasomes are a group of protein complex located in cytoplasm and assemble in response to a wide variety of pathogen-associated molecule patterns, damage-associated molecule patterns, and cellular stress. Generally, the activation of inflammasomes will lead to maturation of proinflammatory cytokines and pyroptotic cell death, both associated with inflammatory cascade amplification. A sensor protein, an adaptor, and a procaspase protein interact through their functional domains and compose one subunit of inflammasome complex. Under physiological conditions, inflammasome functions against pathogen infection and endogenous dangers including mtROS, mtDNA, and so on, while dysregulation of its activation can lead to unwanted results. In recent years, advances have been made to clarify the mechanisms of inflammasome activation, the structural details of them and their functions (negative/positive) in multiple disease models in both animal models and human. The wide range of the stimuli makes the function of inflammasome diverse and complex. Here, we review the structure, biological functions, and therapeutic targets of inflammasomes, while highlight NLRP3, NLRC4, and AIM2 inflammasomes, which are the most well studied. In conclusion, this review focuses on the activation process, biological functions, and structure of the most well-studied inflammasomes, summarizing and predicting approaches for disease treatment and prevention with inflammasome as a target. We aim to provide fresh insight into new solutions to the challenges in this field.

Keywords: AIM2; NLRC4; NLRP3; function; inflammasome; structure; therapy.

FIGURE 1

Overview of the formation and activation process of NLRP3 inflammasome. In the canonical pathway, the activation of NLRP3 is consisted of a priming and activation step. The priming step refers to the binding of PAMPs and DAMPs to PRRs and activation of NF‐κB pathway. The activation step and the assembly of NLRP3 inflammasome lead to the maturation of proinflammatory cytokines and cell pyroptosis. NLRP3 inflammasome can also be activated in noncanonical and alternative pathways.

FIGURE 2

Activation process of AIM2 inflammasome. AIM2 shows high sensitivity recognizing cytoplasm DNA from inner and outer damages. After recognizing dsDNA, AIM2 oligomerize with ASC and procaspase‐1 and form protein complex. Concentration of dsDNA in cytoplasm after bacterial infection can increase through bacteriolysis.

FIGURE 3

Activation process of NLRC4 inflammasome. NLRC4 activation in mice is dependent on NAIPs and responses to bacterial infections. NAIP family members act as pathogen‐sensing proteins. NLRC4 activation can be triggered when purified bacterial flagellin is delivered into cytoplasm.

FIGURE 4

Basic structure of the sensors, adaptor and effector of inflammasomes. Schematic diagram of structure of NAIP and NATCH domain are also shown here. Sensors of inflammasome bind with the adaptor with PYD domain, while the recognition between adaptor and effector is carried out through CARD domain.

FIGURE 5

Inflammasomes work as a bridge between innate and adaptive immunity in immunotherapy for tumors. Inflammasomes play an important role in detection of pathogens in innate immune cells, presenting these danger signals to adaptive immune cells. Inflammasomes also contribute to the development of adaptive immune cells. In tumor‐associated inflammation (TAI), inflammasomes can result in cancer cell death. This figure is created with BioRender.com.