Myeloid cell transmigration across the CNS vasculature triggers IL-1ß-driven neuroinflammation during autoimmune encephalomyelitis in mice

Sébastien A. Lévesque, Alexandre Paré, Benoit Mailhot, Victor Bellver-Landete, Hania Kébir, Marc André Lécuyer, Jorge Ivan Alvarez, Alexandre Prat, Juan Pablo de Rivero Vaccari, Robert W. Keane, Steve Lacroix

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Growing evidence supports a role for IL-1 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), but how it impacts neuroinflammation is poorly understood. We show that susceptibility to EAE requires activation of IL-1R1 on radiation-resistant cells via IL-1ß secreted by bone marrow-derived cells. Neutrophils and monocyte-derived macrophages (MDMs) are the main source of IL-1ß and produce this cytokine as a result of their transmigration across the inflamed blood-spinal cord barrier. IL-1R1 expression in the spinal cord is found in endothelial cells (ECs) of the pial venous plexus. Accordingly, leukocyte infiltration at EAE onset is restricted to IL-1R1+ subpial and subarachnoid vessels. In response to IL-1ß, primary cultures of central nervous system ECs produce GM-CSF, G-CSF, IL-6, Cxcl1, and Cxcl2. Initiation of EAE or subdural injection of IL-1ß induces a similar cytokine/chemokine signature in spinal cord vessels. Furthermore, the transfer of Gr1+ cells on the spinal cord is sufficient to induce illness in EAE-resistant IL-1ß knockout (KO) mice. Notably, transfer of Gr1+ cells isolated from C57BL/6 mice induce massive recruitment of recipient myeloid cells compared with cells from IL-1ß KO donors, and this recruitment translates into more severe paralysis. These findings suggest that an IL-1ß-dependent paracrine loop between infiltrated neutrophils/MDMs and ECs drives neuroinflammation.

Original languageEnglish (US)
Pages (from-to)929-949
Number of pages21
JournalJournal of Experimental Medicine
Volume213
Issue number6
DOIs
StatePublished - May 30 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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