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

Frederico R C Costa; Jefferson A Leite; Diane M Rassi; Josiane F da Silva; Jefferson Elias-Oliveira; Jhefferson B Guimarães; Maria C Foss-Freitas; Niels O S Câmara; Alessandra Pontillo; Rita C Tostes; João S Silva; Daniela Carlos

doi:10.1016/j.celrep.2021.109176

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

Cell Rep. 2021 May 25;35(8):109176. doi: 10.1016/j.celrep.2021.109176.

Affiliations

¹ Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
² Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
³ Department of Clinical Medicine, Internal Medicine Division, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, and Caswell Diabetes Institute University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Immunology, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil; Department of Immunology, Institute of Biomedical Sciences (ICB), University of São Paulo, São Paulo, SP, Brazil.
⁵ Department of Immunology, Institute of Biomedical Sciences (ICB), University of São Paulo, São Paulo, SP, Brazil.
⁶ Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; Fiocruz- Bi-Institutional Translational Medicine Platform, Ribeirão Preto, SP, Brazil.
⁷ Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil. Electronic address: danicar@usp.br.

PMID: 34038731
DOI: 10.1016/j.celrep.2021.109176

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.

Keywords: NLRP1; NOD mouse; STAT-3; STZ; Th17; gut microbiota; immune system; interleukin-17; rs12150220; type 1 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmune Diseases / genetics*
Diabetes Mellitus, Experimental / genetics*
Diabetes Mellitus, Type 1 / genetics*
Humans
Male
Mice
Mice, Inbred NOD
NLR Proteins / metabolism*
Rats
Th17 Cells / immunology*

Substances

NLR Proteins
NLRP1 protein, human