Inflammasomes as therapeutic targets in human diseases

Abstract

Inflammasomes are protein complexes of the innate immune system that initiate inflammation in response to either exogenous pathogens or endogenous danger signals. Inflammasome multiprotein complexes are composed of three parts: a sensor protein, an adaptor, and pro-caspase-1. Activation of the inflammasome leads to the activation of caspase-1, which cleaves pro-inflammatory cytokines such as IL-1β and IL-18, leading to pyroptosis. Effectors of the inflammasome not only provide protection against infectious pathogens, but also mediate control over sterile insults. Aberrant inflammasome signaling has been implicated in the development of cardiovascular and metabolic diseases, cancer, and neurodegenerative disorders. Here, we review the role of the inflammasome as a double-edged sword in various diseases, and the outcomes can be either good or bad depending on the disease, as well as the genetic background. We highlight inflammasome memory and the two-shot activation process. We also propose the M- and N-type inflammation model, and discuss how the inflammasome pathway may be targeted for the development of novel therapy.

Fig. 1

Mechanisms of NLRP3 inflammasome assembly and activation. NLRP3 needs to be primed prior to activation. The priming process includes the binding of PAMPs/DAMPs to TLR or CD36, which promotes the transcription of NLRP3 and IL-1β. The priming event also includes de-ubiquitination of NLRP3. The ubiquitination and phosphorylation of the adaptor protein ASC is also necessary for the assembly of inflammasome. Disruption of the lysosome and release of cathepsin enhances the activation of NLRP3 inflammasome. The assembly of activated inflammasome leads to the processing of pro-caspase-1 into mature and active enzyme, which in turn cleaves pro-IL-1β and pro-IL-18 into active cytokines. Inset: activated NLRP3 binds to ASC through PYD–PYD interactions. Pro-caspase-1 binds to ASC through CARD–CARD interactions

Fig. 2

Mechanisms of NLRC4 inflammasome assembly and activation. The bacterial ligands such as needle protein, rod, and flagellin bind to NAIP proteins. Ligand-bound NAIP then interacts with NLRC4 to form the inflammasome through oligomerization. NLRC4 recruits pro-caspase-1 to the inflammasome via CARD–CARD interaction. Inset: NLRC4 inflammasome components

Fig. 3

The formation and activation of AIM2 inflammasome. The HIN domain of AIM2 binds dsDNA in the cytosol. AIM2 binds to ASC through PYD–PYD interaction. The inflammasome is formed through AIM2-ASC oligomerization. Pro-caspase-1 is recruited by ASC via CARD–CARD interaction. Inset: AIM2 inflammasome components

Fig. 4

Mechanisms of non-canonical inflammasome assembly and activation. Intracellular LPS forms a complex with pro-caspase-11 (mouse) or pro-caspases-4 and -5 (human), which become activated through oligomerization. Activated caspase-4/5/11 induces pyroptosis by cleaving intact GSDMD to generate the N-terminal fragment which forms a pore on membrane. The active mCaspase-11/hCaspase-4 is also involved in the assembly and activation of the NLRP3 inflammasome when PAMP/DAMP signals are present

Fig. 5

Inflammasome activation contributes to the development of diseases. The NLRP3 inflammasome is activated by DAMPs such as ATP, excess glucose, cholesterol, and high fat, leading to the activation of caspase-1 and production of active IL-1β and IL-18 in cardiomyocytes, endothelial cells, and smooth muscle cells. These risk factors are also involved in the development of depression and T2D. CM cardiomyocyte, EC endothelial cell, SMC smooth muscle cell, T2D type 2 diabetes

Fig. 6

Mechanisms underlying the beneficial effect of IL-1 blockade in treating cardiovascular diseases and cancer. The CANTOS trial showed a reduced incidence of CVD in patients treated with canakinumab, a monoclonal antibody blocking IL-1β. The potential mechanisms underlying the beneficial effects of IL-1 targeting strategies include inhibition of cardiomyocyte apoptosis and necrosis, reduction of inflammatory mediator activation in endothelial cells, prevention of recruitment of tumor suppressor cells, and inhibition of tumor angiogenesis and tumor growth. CRP C-reactive protein, CVD cardiovascular disease

Fig. 7

Beneficial effects of acute inflammation and deleterious effects of chronic inflammation. Acute inflammation (M-type) is a beneficial process to destroy pathogens and initiate tissue repair. However, chronic inflammation (N-type) is a pathological condition that lasts for a long time, leading to tissue damage. Both types of inflammation can be modulated by the inflammasome