NLRP1 acts as a negative regulator of Th17 cell programming in mice and humans with autoimmune diabetes
Frederico R. C. Costa, Jefferson Antônio Leite, Diane Meyre Rassi, Josiane F. Silva, Jefferson Elias‐Oliveira, Jhefferson Barbosa Guimarães, Maria Cristina Foss‐Freitas, Niels Olsen Saraiva Câmara, Alessandra Pontillo, Rita C. Tostes, João S. Silva, Daniela Carlos
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β cells. We show here that the protein NOD-like receptor family pyrin domain containing 1 (NLRP1) has a key role in the pathogenesis of mouse and human T1D. More specifically, downregulation of NLRP1 expression occurs during T helper 17 (Th17) differentiation, alongside greater expression of several molecules related to Th17 cell differentiation in a signal transducers and activators of transcription 3 (STAT3)-dependent pathway. These changes lead to a consequent increase in interleukin 17 (IL-17) production within the pancreas and higher incidence of diabetes in streptozotocin (STZ)-injected mice. Finally, in patients with T1D and a SNP (rs12150220) in NLRP1, there is a robust decrease in IL-17 levels in serum and in memory Th17 cells from peripheral blood mononuclear cells. Our results demonstrate that NLRP1 acts as a negative regulator of the Th17 cell polarization program, making it an interesting target for intervention during the early stages of T1D.