title: Interleukin-36γ is expressed by neutrophils and can activate microglia, but has no role in experimental autoimmune encephalomyelitis.
abstract: BACKGROUND
  Experimental autoimmune encephalomyelitis (EAE) is a model of inflammatory demyelinating diseases mediated by different types of leukocytes. How these cells communicate with each other to orchestrate autoimmune attacks is not fully understood, especially in the case of neutrophils, whose importance in EAE is newly established. The present study aimed to determine the expression pattern and role of different components of the IL-36 signaling pathway (IL-36α, IL-36β, IL-36γ, IL-36R) in EAE.
  
  
  METHODS
  EAE was induced by either active immunization with myelin peptide, passive transfer of myelin-reactive T cells or injection of pertussis toxin to transgenic 2D2 mice. The molecules of interest were analyzed using a combination of techniques, including quantitative real-time PCR (qRT-PCR), flow cytometry, Western blotting, in situ hybridization, and immunohistochemistry. Microglial cultures were treated with recombinant IL-36γ and analyzed using DNA microarrays. Different mouse strains were subjected to clinical evaluation and flow cytometric analysis in order to compare their susceptibility to EAE.
  
  
  RESULTS
  Our observations indicate that both IL-36γ and IL-36R are strongly upregulated in nervous and hematopoietic tissues in different forms of EAE. IL-36γ is specifically expressed by neutrophils, while IL-36R is expressed by different immune cells, including microglia and other myeloid cells. In culture, microglia respond to recombinant IL-36γ by expressing molecules involved in neutrophil recruitment, such as Csf3, IL-1β, and Cxcl2. However, mice deficient in either IL-36γ or IL-36R develop similar clinical and histopathological signs of EAE compared to wild-type controls.
  
  
  CONCLUSIONS
  This study identifies IL-36γ as a neutrophil-related cytokine that can potentially activate microglia, but that is only correlative and not contributory in EAE.
authors.affiliation: Axis of Neuroscience, University Hospital Center of Quebec, 2705 Laurier Boulevard, room T2-50, Quebec, QC, G1V 4G2, Canada. lusin357@yahoo.fr.
authors.forename: Lusine
authors.initials: L
authors.lastname: Bozoyan
authors.affiliation: Axis of Neuroscience, University Hospital Center of Quebec, 2705 Laurier Boulevard, room T2-50, Quebec, QC, G1V 4G2, Canada. aline.dumas@crchudequebec.ulaval.ca.
authors.forename: Aline
authors.initials: A
authors.lastname: Dumas
authors.affiliation: Axis of Neuroscience, University Hospital Center of Quebec, 2705 Laurier Boulevard, room T2-50, Quebec, QC, G1V 4G2, Canada. alexandre.patenaude@crchudequebec.ulaval.ca.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Patenaude
authors.affiliation: Axis of Neuroscience, University Hospital Center of Quebec, 2705 Laurier Boulevard, room T2-50, Quebec, QC, G1V 4G2, Canada. Luc.Vallieres@crchul.ulaval.ca.|Department of Molecular Medicine, Laval University, Quebec, Canada. Luc.Vallieres@crchul.ulaval.ca.
authors.forename: Luc
authors.initials: L
authors.lastname: Vallières
mesh_terms: D019264:Adoptive Transfer / Q000009:adverse effects; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000473:pathology*; D007375:Interleukin-1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D009504:Neutrophils / Q000378:metabolism*; D010446:Peptide Fragments / Q000633:toxicity; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D007375:Interleukin-1; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D017472:Receptors, Interleukin-1; C569500:Il1rl2 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55)