IL-6 Inhibition as a Therapeutic Target in Aged Experimental Autoimmune Encephalomyelitis

Abstract

Ageing; Immunosenescence; Multiple sclerosis

Envelliment; Immunosenescència; Esclerosi múltiple

Envejecimiento; Inmunosenescencia; Esclerosis múltiple

Multiple sclerosis (MS) onset at an advanced age is associated with a higher risk of developing progressive forms and a greater accumulation of disability for which there are currently no effective disease-modifying treatments. Immunosenescence is associated with the production of the senescence-associated secretory phenotype (SASP), with IL-6 being one of the most prominent cytokines. IL-6 is a determinant for the development of autoimmunity and neuroinflammation and is involved in the pathogenesis of MS. Herein, we aimed to preclinically test the therapeutic inhibition of IL-6 signaling in experimental autoimmune encephalomyelitis (EAE) as a potential age-specific treatment for elderly MS patients. Young and aged mice were immunized with myelin oligodendrocyte protein (MOG)35–55 and examined daily for neurological signs. Mice were randomized and treated with anti-IL-6 antibody. Inflammatory infiltration was evaluated in the spinal cord and the peripheral immune response was studied. The blockade of IL-6 signaling did not improve the clinical course of EAE in an aging context. However, IL-6 inhibition was associated with an increase in the peripheral immunosuppressive response as follows: a higher frequency of CD4 T cells producing IL-10, and increased frequency of inhibitory immune check points PD-1 and Tim-3 on CD4+ T cells and Lag-3 and Tim-3 on CD8+ T cells. Our results open the window to further studies aimed to adjust the anti-IL-6 treatment conditions to tailor an effective age-specific therapy for elderly MS patients.

This work was funded by the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III and co-funded by the European Union (European Regional Development Fund/European Social Fund) “A way to build Europe” under Grant [PI18/01146] and the “Agència de Gestió d’Ajuts Universitaris i de Recerca” (AGAUR; Generalitat de Catalunya) under Grant [2021SGR782].