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

Korf, Hannelie ; Breser, Laura ; Van Hoeck, Jelter ; Godoy, Janet ; Cook, Dana P ; Stijlemans, Benoit ; De Smidt, Elien ; Moyson, Carolien ; Monteiro Carvalho Mori Cunha, João Paulo LU orcid and Rivero, Virginia , et al. (2017) In PLoS ONE 12(11).
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... (More)

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.

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type
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publication status
published
subject
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
in
PLoS ONE
volume
12
issue
11
article number
e0187455
publisher
Public Library of Science (PLoS)
external identifiers
  • pmid:29095944
  • scopus:85033407205
ISSN
1932-6203
DOI
10.1371/journal.pone.0187455
language
English
LU publication?
no
id
19145018-b855-4528-8bcf-2a28f2a4d70e
date added to LUP
2019-09-18 13:33:16
date last changed
2024-06-12 01:24:59
@article{19145018-b855-4528-8bcf-2a28f2a4d70e,
  abstract     = {{<p>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.</p>}},
  author       = {{Korf, Hannelie and Breser, Laura and Van Hoeck, Jelter and Godoy, Janet and Cook, Dana P and Stijlemans, Benoit and De Smidt, Elien and Moyson, Carolien and Monteiro Carvalho Mori Cunha, João Paulo and Rivero, Virginia and Gysemans, Conny and Mathieu, Chantal}},
  issn         = {{1932-6203}},
  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}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{11}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS ONE}},
  title        = {{MIF inhibition interferes with the inflammatory and T cell-stimulatory capacity of NOD macrophages and delays autoimmune diabetes onset}},
  url          = {{http://dx.doi.org/10.1371/journal.pone.0187455}},
  doi          = {{10.1371/journal.pone.0187455}},
  volume       = {{12}},
  year         = {{2017}},
}