031 – Endothelial IL-6 signaling is critical for leukocyte recruitment and activation in a model of autoimmune demyelination

Printed Poster | Session 2

031 – Endothelial IL-6 signaling is critical for leukocyte recruitment and activation in a model of autoimmune demyelination

Noopur Singh (1, 2) – Aline Dumas (1) – Jean-François Richard (1) – Luc Vallières (1, 2)
Neuroscience Unit, University Hospital Centre of Quebec – Laval University, Quebec, Canada (1) – Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec, Canada (2)


Interleukin-6 (IL-6) is essential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis and optic neuromyelitis. In addition to its known role in the differentiation of self-reactive TH17 lymphocytes, IL-6 acts on the endothelium of blood vessels in the central nervous system (CNS) to stimulate the recruitment and activation of myeloid cells such as; neutrophils, macrophages, and dendritic cells. We tested this hypothesis by blocking the signaling of IL-6 specifically in the endothelium. Mice expressing Cre recombinase under the control of Tie2 endothelial promoter were crossed with mice in which the receptor IL-6 alpha gene had LoxP recombination sites. These mice were used to study the development of EAE, leukocyte recruitment and expression of inflammatory genes responsible for myeloid cells recruitment and activation, sequentially driving them for antigen presentation. Our findings demonstrate that endothelial cells in the CNS express the IL-6 receptor. The specific elimination of IL-6 receptor alpha in the endothelium largely delays the onset of EAE with very low incidence, and the leukocyte recruitment is blocked. It is noteworthy that the differences observed by deletion of IL-6 receptor are due to reduction in the number of ICAM1 expressing extravascular myeloid antigen presenting cells. Furthermore, we identify CXCL1, a neutrophil specific chemokine and PTGS2 (COX-2), a prostaglandin synthesizing enzyme as the key endothelial genes induced by IL-6 to recruit and activate the myeloid cells during pre-onset stages of EAE. Hence, we conclude that IL-6 plays a critical secondary role during pre-onset stages of EAE by binding to IL-6 receptor of CNS endothelium, which in turn activates the endothelial cells for up-regulation of the chemokines and prostaglandin synthesizing enzymes responsible for leukocyte recruitment and activation, a potential mechanism that could be targeted to treat autoimmune demyelinating diseases.