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

Hannelie Korf, Laura Breser, Jelter Van Hoeck, Janet Godoy, Dana P Cook, Benoit Stijlemans, Elien De Smidt, Carolien Moyson, João Paulo Monteiro Carvalho Mori Cunha, Virginia Rivero, Conny Gysemans, Chantal Mathieu

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

9 Citeringar (SciVal)

Sammanfattning

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.

Originalspråkengelska
Artikelnummere0187455
TidskriftPLoS ONE
Volym12
Utgåva11
DOI
StatusPublished - 2017 nov. 2
Externt publiceradJa

Ämnesklassifikation (UKÄ)

  • Cell- och molekylärbiologi
  • Endokrinologi och diabetes

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