Interleukin-26, preferentially produced by T <sub>H</sub> 17 lymphocytes, regulates CNS barrier function
Bieke Broux, Stéphanie Zandee, Elizabeth Gowing, Marc Charabati, Marc‐André Lécuyer, Olivier Tastet, Lamia Hachehouche, Lyne Bourbonnière, Jean-Philippe Ouimet, Florent Lemaître, Sandra Larouche, Romain Cayrol, Alain Bouthillier, Robert Moumdjian, Boaz Lahav, Josée Poirier, Pierre Duquette, Nathalie Arbour, Evelyn Peelen, Alexandre Prat
Abstract
<h3>Objective</h3> To investigate the involvement of interleukin (IL)-26 in neuroinflammatory processes in multiple sclerosis (MS), in particular in blood-brain barrier (BBB) integrity. <h3>Methods</h3> Expression of IL-26 was measured in serum, CSF, in vitro differentiated T helper (T<sub>H</sub>) cell subsets, and postmortem brain tissue of patients with MS and controls by ELISA, quantitative PCR, and immunohistochemistry. Primary human and mouse BBB endothelial cells (ECs) were treated with IL-26 in vitro and assessed for BBB integrity. RNA sequencing was performed on IL-26–treated human BBB ECs. Myelin oligodendrocyte glycoprotein<sub>35–55</sub> experimental autoimmune encephalomyelitis (EAE) mice were injected IP with IL-26. BBB leakage and immune cell infiltration were assessed in the CNS of these mice using immunohistochemistry and flow cytometry. <h3>Results</h3> IL-26 expression was induced in T<sub>H</sub> lymphocytes by T<sub>H</sub>17-inducing cytokines and was upregulated in the blood and CSF of patients with MS. CD4<sup>+</sup>IL-26<sup>+</sup> T lymphocytes were found in perivascular infiltrates in MS brain lesions, and both receptor chains for IL-26 (IL-10R2 and IL-20R1) were detected on BBB ECs in vitro and in situ. In contrast to IL-17 and IL-22, IL-26 promoted integrity and reduced permeability of BBB ECs in vitro and in vivo. In EAE, IL-26 reduced disease severity and proinflammatory lymphocyte infiltration into the CNS, while increasing infiltration of Tregs. <h3>Conclusions</h3> Our study demonstrates that although IL-26 is preferentially expressed by T<sub>H</sub>17 lymphocytes, it promotes BBB integrity in vitro and in vivo and is protective in chronic EAE, highlighting the functional diversity of cytokines produced by T<sub>H</sub>17 lymphocytes.