Regulation of inflammasome activity

Abstract

Interleukin-1beta (IL-1beta) is a potent inflammatory cytokine, which is implicated in acute and chronic inflammatory disorders. The activity of IL-1beta is regulated by the proteolytic cleavage of its inactive precursor resulting in the mature, bioactive form of the cytokine. Cleavage of the IL-1beta precursor is performed by the cysteine protease caspase-1, which is activated within protein complexes termed 'inflammasomes'. To date, four distinct inflammasomes have been described, based on different core receptors capable of initiating complex formation. Both the host and invading pathogens need to control IL-1beta production and this can be achieved by regulating inflammasome activity. However, we have, as yet, little understanding of the mechanisms of this regulation. In particular the negative feedbacks, which are critical for the host to limit collateral damage of the inflammatory response, remain largely unexplored. Recent exciting findings in this field have given us an insight into the potential of this research area in terms of opening up new therapeutic avenues for inflammatory disorders.

Figure 1

Schematic representation of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family of receptors and additional inflammasome components. The typical tripartite structure of NLRs is shown: the effector domain [which can be either a pyrin domain (PYD), a caspase recruitment domain (CARD) or a baculovirus IAP repeat (BIR) domain], the central NACHT [NAIP (NLR family, apoptosis inhibitory protein), CIITA (class II, major histocompatibility complex, transactivator), HET-E (plant het gene product involved in vegetative incompatibility) and TP-1 (telomerase-associated protein 1)] domain and the C-terminal LRR. The majority of the NLRs also contain a NACHT-associated domain (NAD). The NLRs are further subdivided into three categories: the NLR family, pyrin domain containing (NLRP), characterized by an N-terminal PYD, the NODs, which have an N-terminal CARD and NLR family, CARD containing 4 (NLRC4)/NAIP, two proteins which often accomplish common tasks. The NLRP3 structure is representative of NLRP2–14, with the exception of NLRP10 that lacks the leucine-rich repeats (LRRs). Absent in melanoma 2 (AIM2) belongs to the haematopoietic interferon-inducible nuclear protein (HIN) family of proteins, and has the characteristic N-terminal PYD and a C-terminal HIN domain. The adaptor protein apoptosis speck protein with CARD (ASC) consists of a PYD and a CARD, important for homotypic CARD–CARD interactions with caspase-1.

Figure 2

Schematic representation of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain containing (NLRP3) and absent in melanoma 2 (AIM2) inflammasome complexes. Two prototypical inflammasomes are depicted; while NLRP3 is believed to change conformation and to oligomerize upon ligand sensing, AIM2 is thought to form its complex around its ligand double-stranded (ds) DNA. Caspase-1 is recruited into the complex via the adaptor protein apoptosis speck protein with CARD (ASC). Once in close proximity within the inflammasome complex, caspases are activated through autoproteolytic cleavage and can then process their substrates, as for instance pro-interleukin-1β (proIL-1β).