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.

Single-Nucleotide Variants in the AIM2 – Absent in Melanoma 2 Gene (rs1103577) Associated With Protection for Tuberculosis

“…In the early stage of infection, innate immune response is essential to ensure the success of control and elimination of bacilli. Subsequently, upon inflammasomes activation, proinflammatory cytokines are released to keep in check the invading pathogen ( 45 ). In this context, we have focus on one SNV in the AIM2 inflammasome in tuberculosis together with two other SNVs, one in CARD8 and one in CTSB , that are related to NLRP3 pathway.…”

“…Studies regarding human genetic variants of AIM2 are rare in infectious diseases ( 41 , 42 , 45 ). Recently, we investigated another SNV of AIM2 (rs35130877) in 288 patients with PTB and 288 HCs.…”

“…Several studies have shown a genetic predisposition to development of TB ( 40 – 44 ). Genetic variant in inflammasomes can change their physiological function and contribute to the susceptibility, severity, and outcomes of TB ( 45 ). Single-nucleotide variant (SNV) of NLRP3 (rs10754558) and SNV of P2X7 (rs2230911) are associated with TB.…”

NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity

“…Several paradoxical conclusions exist on the same drug in different studies, which may be due to different methods, cell types, animal models, and dosage regimens. In addition, many pathway responses to different inflammasomes are interrelated and overlapping (Fernandes et al, 2020), and underappreciated inflammasomes can also drive IL-1β and IL-18 secretion in response to stimuli (Broz and Dixit, 2016). Technical limitations, such as the absence of conditional NLRP3 gene knockout and the lack of in vivo validation for in vitro results, also lead to conflicting conclusions.…”

Inflammasome as an Effective Platform for Fibrosis Therapy

“…1 Inflammasome regulates the secretion of IL-1β and IL-18, both of which are vital for repairing of damaged tissues and play an important role in fibrosis. 2,3 Fibrosis is the last stage of a chronic inflammatory response caused by factors such as chemical damage, autoimmune reactions, radiation, allergic reactions, and infections. It can occur in many organs and is characterized by excessive deposition of the extracellular matrix (ECM).…”