MIF inhibition interferes with the inflammatory and T cell-stimulatory capacity of NOD macrophages and delays autoimmune diabetes onset

Research output: Contribution to journalArticle

Abstract

Macrophages contribute in the initiation and progression of insulitis during type 1 diabetes (T1D). However, the mechanisms governing their recruitment into the islets as well as the manner of retention and activation are incompletely understood. Here, we investigated a role for macrophage migration inhibitory factor (MIF) and its transmembrane receptor, CD74, in the progression of T1D. Our data indicated elevated MIF concentrations especially in long-standing T1D patients and mice. Additionally, NOD mice featured increased MIF gene expression and CD74+ leukocyte frequencies in the pancreas. We identified F4/80+ macrophages as the main immune cells in the pancreas expressing CD74 and showed that MIF antagonism of NOD macrophages prevented their activation-induced cytokine production. The physiological importance was highlighted by the fact that inhibition of MIF delayed the onset of autoimmune diabetes in two different diabetogenic T cell transfer models. Mechanistically, macrophages pre-conditioned with the MIF inhibitor featured a refractory capacity to trigger T cell activation by keeping them in a naïve state. This study underlines a possible role for MIF/CD74 signaling pathways in promoting macrophage-mediated inflammation in T1D. As therapies directed at the MIF/CD74 pathway are in clinical development, new opportunities may be proposed for arresting T1D progression.

Details

Authors
External organisations
  • National University of Cordoba, Argentina
  • Catholic University of Leuven
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
  • Endocrinology and Diabetes

Keywords

  • Animals, Antigens, Differentiation, B-Lymphocyte/immunology, Diabetes Mellitus, Type 1/immunology, Female, Histocompatibility Antigens Class II/immunology, Humans, Lymphocyte Activation/immunology, Macrophage Migration-Inhibitory Factors/antagonists & inhibitors, Macrophages/immunology, Mice, Mice, Inbred NOD, T-Lymphocytes
Original languageEnglish
Article numbere0187455
JournalPLoS ONE
Volume12
Issue number11
Publication statusPublished - 2017 Nov 2
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes