Myelin-specific T cells induce interleukin-1beta expression in lesion-reactive microglial-like cells in zones of axonal degeneration

Manuela Grebing, Helle H Nielsen, Christina D Fenger, Katrine T Jensen, Christian U von Linstow, Bettina H Clausen, Anders Martin Söderman, Kate L Lambertsen, Mads Thomassen, Torben A Kruse, Bente Finsen

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Infiltration of myelin-specific T cells into the central nervous system induces the expression of proinflammatory cytokines in patients with multiple sclerosis (MS). We have previously shown that myelin-specific T cells are recruited into zones of axonal degeneration, where they stimulate lesion-reactive microglia. To gain mechanistic insight, we used RNA microarray analysis to compare the transcript profile in hippocampi from perforant pathway axonal-lesioned mice with and without adoptively transferred myelin-specific T cells 2 days postlesion, when microglia are clearly lesion reactive. Pathway analysis revealed that, among the 1,447 differently expressed transcripts, the interleukin (IL)-1 pathway including all IL-1 receptor ligands was upregulated in the presence of myelin-specific T cells. Quantitative polymerase chain reaction showed increased mRNA levels of IL-1β, IL-1α, and IL-1 receptor antagonist in the T-cell-infiltrated hippocampi from axonal-lesioned mice. In situ hybridization and immunohistochemistry showed a T-cell-enhanced lesion-specific expression of IL-1β mRNA and protein, respectively, and induction of the apoptosis-associated speck-like protein, ASC, in CD11b + cells. Double in situ hybridization showed colocalization of IL-1β mRNA in a subset of CD11b mRNA + cells, of which many were part of cellular doublets or clusters, characteristic of proliferating, lesion-reactive microglia. Double-immunofluorescence showed a T-cell-enhanced colocalization of IL-1β to CD11b + cells, including lesion-reactive CD11b + ramified microglia. These results suggest that myelin-specific T cells stimulate lesion-reactive microglial-like cells to produce IL-1β. These findings are relevant to understand the consequences of T-cell infiltration in white and gray matter lesions in patients with MS. GLIA 2016;64:407-424 Main points: CNS infiltrating myelin specific T cells stimulate lesion-reactive microglial-like cells to increase their transcription of IL-1β mRNA and the translation of pro-IL-1β into mature IL-1β. This is of relevance to better understand the pathogenic effect of T cells in multiple sclerosis.

Original languageEnglish
JournalGlia
Volume64
Issue number3
Pages (from-to)407-424
ISSN0894-1491
DOIs
Publication statusPublished - Mar 2016

Bibliographical note

Online Version of Record published before inclusion in an issue

Keywords

  • Cytokines
  • Demyelination
  • Gray matter
  • Multiple sclerosis
  • Wallerian degeneration
  • Axons/metabolism
  • Adoptive Transfer
  • Fluoresceins/metabolism
  • Microglia/pathology
  • Neutrophil Infiltration
  • Dentate Gyrus/pathology
  • Neurodegenerative Diseases/pathology
  • Signal Transduction/physiology
  • Microarray Analysis
  • T-Lymphocytes/physiology
  • Cytokines/genetics
  • Female
  • Disease Models, Animal
  • RNA, Messenger/metabolism
  • Animals
  • Analysis of Variance
  • Interleukin-1beta/genetics
  • Mice
  • Myelin Sheath/pathology
  • Up-Regulation/genetics

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