Inflammasome genetics and complex diseases: a comprehensive review

Abstract

The inflammasome is a cytoplasmic multiprotein complex responsible for the activation of inflammatory caspases (caspase-1, -4, and -5) in response to pathogen- and/or damage-associated molecular patterns or to homeostasis-altering molecular pathways, and for the consequent release of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-18. Taking in account the complexity of inflammasome activation and that several regulatory steps are involved in maintaining its physiologic role in homeostasis and innate immune response, it does not surprise that several genetic variants in inflammasome components have been associated with common pathologies in the general population, such as autoimmune disorders, cardiovascular diseases, obesity and associated metabolic syndrome, neurodegenerative diseases, and cancer. Moreover, the susceptibility to infectious agents and/or to develop severe complications during infections also has been related to inflammasome genetics. In this work, we revised genetic association studies about polymorphisms of main inflammasome genes in sterile as well as infectious diseases, trying to depict the genetic contribution of inflammasome in disease pathogenesis.

Fig. 1. Basic inflammasome composition and role in immune response.

Pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and/or homeostasis-altering associated patterns (HAMPs) are sensed by a plethora of cytosolic receptors containing a central NACHT domain, a C-terminal LRRs domain and a N-terminal PYD or CARD domain (NLRs), or a N-terminal PYD domain together with other domains such as B box zinc finger (bz, BB), coiled coil (CC) and B30.2/SPRY as for pyrin, or HIN-200 motifs as for PYD and HIN containing receptors (PYHINs). Once activated by a molecular pattern, receptors recrute directly, through homotypic CARD–CARD domains interaction, or indirectly, through the recruitment of the adaptor molecule PYD-CARD or ASC, an inflammatory caspase (namely, caspase-1, -4, and -5) which, in turn, cleaves biologically inactive forms of IL-1ß, IL-18 (pro-IL-1ß, pro-IL-18, respectively) and gasdermin-D (GSDM-D). Inflammasome activation results in the release of pro-inflammatory cytokines IL-1ß and IL-18, and a cleaved form of GSDM-D which creates pores within cellular membrane and it is responsible for cytokines release and, in some cases, for pyroptosis. IL-1ß and IL-18 mediate inflammatory process and adaptive immunity response. Moreover, IL-18 is also important for epithelia and mucosal homeostasis.

Fig. 2. Main inflammasome genes structure and polymorphisms localization.

Exon and domain structures are reported for NLRP1/NLRP1 (a), NLRP3/NLRP3 (b), NLRC4/NLRC4 (c), MEFV/pyrin (d), AIM2/AIM2 and IFI16/IFI16 (e). Exons size is proportional within each coding region. Introns size is not proportional. Amino acid number is indicated above main domains. PYD pyrin domain, NACHT nucleotide-binding domain and oligomerization domain, LRRs leucine-rich repeats, FIIND function-to-find domain, CARD caspase-recruitment domain, Bz zinc finger, BB B box, CC coiled coil, B30.2/SPRY SPRY domain, HIN-200 HIN-200 domain.

Fig. 3. Main disease-associated risk variants identified in noninfectious sterile diseases.

Stacked bar plots showing disease-associated risk SNPs for each disease group: cancer, cardiovascular diseases (CVD), fibrosis, hypersensitivity and allergic diseases, metabolic diseases, neurologic diseases, pregnancy disorders, skin and mucosal diseases. Risk or protection effect of NLRP1, NLRP3, CARD8, MEFV, CASP1, and CASP5 genes is represented as positive or negative bars, respectively.

Fig. 4. Interpretation of inflammasome genetic data.

a Main expression sites for inflammasome receptors are reported together with preferential cytokine processing (higher and bold characters). Alternative function of inflammasome receptors is eventually indicated. Expression data were obtained from public databases (https://www.GTEX.org and/or https://www.proteinatlas.org). b Schematic representation of the effect of inflammasome genetic variants on the constitutive inflammasome activation rate, and the consequent role in disease predisposition, taking in account that inflammasome genes have often distinct cell/tissue-specific expression.