Role of Genetic Alterations in the NLRP3 and CARD8 Genes in Health and Disease

Abstract

The complexity of a common inflammatory disease is influenced by multiple genetic and environmental factors contributing to the susceptibility of disease. Studies have reported that these exogenous and endogenous components may perturb the balance of innate immune response by activating the NLRP3 inflammasome. The multimeric NLRP3 complex results in the caspase-1 activation and the release of potent inflammatory cytokines, like IL-1β. Several studies have been performed on the association of the genetic alterations in genes encoding NLRP3 and CARD8 with the complex diseases with inflammatory background, like inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis, and type 1 diabetes. The aim of the present review is therefore to summarize the literature regarding genetic alterations in these genes and their association with health and disease.

NLRP3 inflammasome driven liver injury and fibrosis: Roles of IL‐17 and TNF in mice

“…Although IL‐17 production can be regulated by NLRP3 activation, TNF production is mainly thought to occur through signals that lead to activation of nuclear factor kappa B . NLRP3 activation may amplify this production in an autocrine or paracrine fashion by inducing the maturation and release of IL‐1β and IL‐18, which then interact with their own membrane receptors . Furthermore, both cytokines have been involved in creating an autoinflammatory loop that characterizes these disorders, whereas IL‐17 is an important contributor for tissue recruitment of neutrophils, a central feature found in livers of mice with constitutive active NLRP3.…”

Association of nod‐like receptor protein‐3 single nucleotide gene polymorphisms and expression with the susceptibility to relapsing–remitting multiple sclerosis

“…These polymorphisms are suggested to be associated with the basal levels of IL‐1β and IL‐18. The G allele in rs10754558 was shown to enhance NLRP3 mRNA stability, leading to increased IL‐1 and IL‐18 secretion (Paramel, Sirsjo, & Fransen, ; Verma et al, ). Moreover, functional analysis has demonstrated that the mutant alleles of rs10754558 and rs4612666 could lead to the increment of the NLRP3 mRNA stability and enhanced the NLRP3 expression (Hitomi et al, ).…”

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

“…In addition to these autoactivating NLRP3 mutations associated with CAPS, single nucleotide polymorphisms in NLRP3 have been associated with increased caspase‐1 activity in common diseases, such as Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, and celiac disease . The importance of NLRP3 inflammasome‐mediated activation of IL‐1β and IL‐18 in the pathogenesis of common diseases has largely been validated in preclinical models, including models of Alzheimer's disease, acute graft‐versus‐host‐disease, multiple sclerosis, liver inflammation and fibrosis, gout, obesity and type 2 diabetes, and cardiovascular disease (e.g., atherosclerosis) .…”