Inflammasomes and Type 1 Diabetes

Abstract

Microbiota have been identified as an important modulator of susceptibility in the development of Type 1 diabetes in both animal models and humans. Collectively these studies highlight the association of the microbiota composition with genetic risk, islet autoantibody development and modulation of the immune responses. However, the signaling pathways involved in mediating these changes are less well investigated, particularly in humans. Importantly, understanding the activation of signaling pathways in response to microbial stimulation is vital to enable further development of immunotherapeutics, which may enable enhanced tolerance to the microbiota or prevent the initiation of the autoimmune process. One such signaling pathway that has been poorly studied in the context of Type 1 diabetes is the role of the inflammasomes, which are multiprotein complexes that can initiate immune responses following detection of their microbial ligands. In this review, we discuss the roles of the inflammasomes in modulating Type 1 diabetes susceptibility, from genetic associations to the priming and activation of the inflammasomes. In addition, we also summarize the available inhibitors for therapeutically targeting the inflammasomes, which may be of future use in Type 1 diabetes.

Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment

“…Although the Human leukocyte antigen (HLA) genes are known to have a role in the development of T1D, evidence have continued to indicate that the pro-inflammatory IL-18 contributes to the genetic susceptibility to T1D ( 150 ). Studies in both humans and mice have revealed that IL-18 genes are localized in chromosome areas associated with T1D susceptibility ( 151 ). Comprising of six exons and five introns, the IL-18 gene is located on chromosome 11q22.2-q22.3 ( 152 ).…”

The regulation of self-tolerance and the role of inflammasome molecules

“…On the other hand, reduced NLRP3 expression in colonic NOD mouse tissue is associated with decreased microbiota dysbiosis, enhanced intestinal barrier function and diabetes prevention ( 125 , 126 ). It is well established that dysbiosis within the gut microbiota significantly affects disease progression in NOD mice, and clinical findings suggest similar effects may also occur in T1D subjects ( 16 , 205 , 212 – 215 ). These studies provide evidence that inflammasomes may play a key role in regulating T1D progression in part via effects on gut microbiota and intestinal barrier function ( 16 ).…”

“…It is well established that dysbiosis within the gut microbiota significantly affects disease progression in NOD mice, and clinical findings suggest similar effects may also occur in T1D subjects ( 16 , 205 , 212 – 215 ). These studies provide evidence that inflammasomes may play a key role in regulating T1D progression in part via effects on gut microbiota and intestinal barrier function ( 16 ). Studies have reported that gut microbiota composition and/or intestinal barrier permeability are also influenced by other inflammasome molecules such as NLRP6 ( 216 ), NLRC4 ( 217 ), NLRX1 ( 218 , 219 ), and NLRP12 ( 220 , 221 ).…”

“…Events driving caspase-1 activation, IL-1β and IL-18 maturation, and induction of pyroptosis and/or PANoptosis then follow ( 11 , 12 ). To date, the role of inflammasomes in autoimmunity have largely focused on NLRP3 and AIM2, but other inflammasome molecules such as NLRP1, and NLR family CARD domain-containing protein 4 (NLRC4) have also been implicated in autoimmunity ( 16 , 17 ). The respective inflammasomes are defined by the sensor protein.…”

“…The initiation and progression of T1D are influenced by genetic and poorly defined environmental factors ( 201 – 204 ). The latter include viral infections, and dysbiosis of gut microbiota, which are events that can be impacted by inflammasome activity ( 16 , 201 , 205 ).…”