Abstract
BackgroundExperimental 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.MethodsEAE 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.ResultsOur 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.ConclusionThis study identifies IL-36γ as a neutrophil-related cytokine that can potentially activate microglia, but that is only correlative and not contributory in EAE.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0392-7) contains supplementary material, which is available to authorized users.
Highlights
Experimental autoimmune encephalomyelitis (EAE) is a model of inflammatory demyelinating diseases mediated by different types of leukocytes
For example: GM-CSF derives from T cells and promotes dendritic cell recruitment [20, 21], IL-12 and IL-23 are secreted by dendritic cells to sustain T cell activation [22], and IL-1β is released from different myeloid cells to induce inflammatory responses [23]
The findings presented below demonstrate that IL-36γ is and strongly expressed by neutrophils in both central nervous system (CNS) and hematopoietic compartments during certain forms of EAE and that microglia can react to IL-36γ by releasing neutrophil-related cytokines; IL-36γ does not influence the clinical and histopathological signs of EAE
Summary
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. Bozoyan et al Journal of Neuroinflammation (2015) 12:173 such as interleukins, chemokines, and growth factors. Many of these molecules have been studied in the context of EAE in the hope of identifying potential therapeutic targets. The IL-36 proteins exhibit a typical β-trefoil structure [26] whose activity is enhanced by N-terminal truncation [27]
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