NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets

Abstract

Studies in animal models and human subjects have shown that both innate and adaptive immunity contribute to the pathogenesis of type 1 diabetes (T1D). Whereas the role of TLR signaling pathways in T1D has been extensively studied, the contribution of the nucleotidebinding oligomerization domain, leucine-rich repeat and pyrin domaincontaining protein (NLRP) 3 inflammasome pathway remains to be explored. In this study, we report that NLRP3 plays an important role in the development of T1D in the nonobese diabetic (NOD) mouse model. NLRP3 deficiency not only affected T-cell activation and Th1 differentiation, but also modulated pathogenic T-cell migration to the pancreatic islet. The presence of NLRP3 is critical for the expression of the chemokine receptors CCR5 and CXCR3 on T cells. More importantly, NLRP3 ablation reduced the expression of chemokine genes CCL5 and CXCL10 on pancreatic islet cells in an IRF-1-dependent manner. Our results suggest that molecules involved in chemotaxis, accompanied by the activation of the NLRP3 inflammasome, may be effective targets for the treatment of T1D.NLRP3 | islet | type 1 diabetes | chemokine | NOD mouse

Nucleotide-binding oligomerization domain-containing protein 2 (Nod2) modulates T1DM susceptibility by gut microbiota

“…We recently showed that NLRP3 alters T1DM development by limiting the recruitment and infiltration of autoreactive CD4 + T-cells into the pancreas [15]. Our current study provides evidence that NLR signaling is important for modulating diabetes susceptibility by alteration of the microbial composition, which in turn affects the phenotype and functions of immune cells.…”

“…However, much less is known about the role of NLR family members in T1DM susceptibility, in humans and mice. We recently reported that NLRP3, an important inflammasome component, influences T1DM development by regulating chemokines and their receptors in both immune cells and islet beta cells, preventing immune cell migration to the targeted tissue [15].…”

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

“…It was recently shown that ablation of Nlrp3 expression in pancreatic islets, comprised of nonhematopoietic cells, can compromise migration of immune cells to pancreatic islets (49). This raises the possibility that nonhematopoietic cochlear cells can also express NLRP3/Nlrp3 and contribute to cochlear autoinflammation in humans with DFNA34 or CAPS.…”

The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes

“…However, mechanistic studies are currently under investigation. To investigate the role of the inflammasome in the immuno-pathogenesis of T1D development, we developed NLRP3-deficient NOD mice [129]. In the absence of NLRP3, NOD mice developed a reduced incidence of T1D.…”