4.8 Article

NLRP1 acts as a negative regulator of Th17 cell programming in mice and humans with autoimmune diabetes

Journal

CELL REPORTS
Volume 35, Issue 8, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2021.109176

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Funding

  1. Sao Paulo Research Foundation (FAPESP) [2013/08216-2, 12/10395-02, 18/14815-0, 16/10641]
  2. FAEPA (Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto)
  3. CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior)
  4. Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [18/14815-0] Funding Source: FAPESP

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NLRP1 plays a crucial role in the pathogenesis of T1D by regulating the Th17 cell polarization program and affecting the production of IL-17, leading to pancreatic destruction and increased risk of diabetes.
Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic beta 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.

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