Inflammasomes in neurodegenerative diseases

Abstract

Inflammasomes represent a crucial component of the innate immune system, which respond to threats by recognizing different molecules. These are known as pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs). In neurodegenerative diseases and neuroinflammation, the accumulation of misfolded proteins, such as beta-amyloid and alpha-synuclein, can lead to inflammasome activation, resulting in the release of interleukin (IL)-1β and IL-18. This activation also induces pyroptosis, the release of inflammatory mediators, and exacerbates neuroinflammation. Increasing evidence suggests that inflammasomes play a pivotal role in neurodegenerative diseases. Therefore, elucidating and investigating the activation and regulation of inflammasomes in these diseases is of paramount importance. This review is primarily focused on evidence indicating that inflammasomes are activated through the canonical pathway in these diseases. Inflammasomes as potential targets for treating neurodegenerative diseases are also discussed.

Keywords: Inflammasome; Microglia; Neurodegeneration; Neurodegenerative diseases; Neuroinflammation.

Fig. 1

Structure of human inflammasomes and inflammasome complexes. a Schematic of compositions of NLRP3, NLRP1, NLRC4, AIM2 and Pyrin. b Apoptosis-Associated Speck-Like Protein (ASC) is composed of a PYD and a CARD. Caspase-1 consists of a CARD and a middle portion that includes the p20 and p10 subunits. c Upon inflammasome activation by various stimuli, homotypic PYD-PYD and CARD-CARD interactions facilitate the recruitment of ASC and the activation of caspase-1. Ultimately, oligomerization leads to the formation of the inflammasome complex, producing active caspase-1, which cleaves pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18, and cleaves gasdermin D, forming pores to release cytokines, leading to pyroptosis. AIM2, absent in melanoma 2; CARD, caspase recruitment domain; FIIND, function-to-find domain; HIN-200, hemopoietic IFN-inducible nuclear proteins with 200-amino acid motif; LRR, leucine-rich repeat sequences; NACHT: NAIP (neuronal apoptosis inhibitor protein), CIITA (class II transactivator), HET-E (invariant chain of the MHC class II), and TP1 (telomerase-associated protein); NLRC4: Nod-like receptor and caspase recruitment domain-containing protein 4; NLRP: Nod-like receptor and pyrin domain-containing protein; PYD, pyrin domain

Fig. 2

Inflammasome activation in neurodegenerative diseases. In neurodegenerative diseases, pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs) activate Toll-like receptors (TLRs). TLR activation induces expression of NLRP3, pro-IL-1β, and pro-IL-18 through nuclear factor-kB (NF-kB) transcription. The intracellular NLRP3 is activated by pathological proteins or DAMPs, NLRP1 recognizes dsRNA and viral proteases, NLRC4 identifies bacterial flagellin, AIM2 is specifically activated by dsDNA, and Pyrin recognizes RhoA-inhibiting microbial toxins. Following priming, the inflammasome undergoes activation upon perception of endogenous or exogenous signals, which in turn promote the recruitment of ASC and activation of caspase-1, leading to the formation of an inflammasome complex. Subsequently, the active caspase-1 cleaves pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18, and cleaves gasdermin D, forming membrane pores to release cytokines, thereby initiating pyroptosis. AIM2, absent in melanoma 2; NLRC4: Nod-like receptor and caspase recruitment domain-containing protein 4; NLRP1: Nod-like receptor and pyrin domain-containing protein 1; NLRP3: Nod-like receptor and pyrin domain-containing protein 3

Fig. 3

Neuroinflammation caused by inflammasome activation. Inflammasome activation has been observed in numerous neurodegenerative diseases, the majority of which are attributed to aberrant aggregation of misfolded proteins, resulting in inflammasome activation. In Alzheimer’s disease, the pathological hallmarks are the deposition of beta-amyloid protein and hyperphosphorylation of tau protein. In Parkinson’s disease, the underlying mechanism involves the aberrant aggregation of alpha-synuclein (α-Syn). In Huntington’s disease, the underlying cause is the aberrant aggregation of the huntingtin protein (HTT) and the mutated form of this protein, mHTT. In amyotrophic lateral sclerosis, the underlying mechanism involves the aberrant aggregation of TDP-43 and SOD1 proteins. In multiple sclerosis, peripheral immune cells, namely T cells and B cells, infiltrate the central nervous system through the damaged blood–brain barrier, thereby activating inflammasomes. Following inflammasome activation, active caspase-1 cleaves pro-IL-1β and pro-IL-18, resulting in the production of mature IL-1β and IL-18. These mature cytokines serve as principal mediators of chronic inflammation in neurodegenerative diseases. Moreover, active caspase-1 also cleaves gasdermin D, resulting in the formation of pores on the cell membrane, leading to release of cellular contents into the extracellular environment and induction of pyroptosis