In Silico and In Vivo Analysis of IL37 in Multiple Sclerosis Reveals Its Probable Homeostatic Role on the Clinical Activity, Disability, and Treatment with Fingolimod.

Eugenio Cavalli,Jovana Ivanovic,Sarlota Mesaros,Vanja Martinovic,Manuela Pennisi,Maria Sofia Basile,Jelena Drulovic,Emanuela Mazzon,Maria Cristina Petralia,Paolo Fagone,Reni Kalfin,Santa Mammana,Tatjana Pekmezovic,Marko Andabaka,Ferdinando Nicoletti

doi:10.3390/molecules25010020

Abstract

We evaluated the in silico expression and circulating levels of interleukin (IL)37 in patients with different forms of multiple sclerosis (MS) and also upon treatment with different disease-modifying drugs. The combined interpretation of the resulting data strengthens and extends the current emerging concept that endogenous IL37 plays an important role in determining onset and progression of MS. The in silico analysis revealed that production of IL37 from cluster of differentiation (CD)4+ T cells from MS patients was reduced in vitro as compared to healthy controls. The analysis of the datasets also demonstrated that “higher” levels of IL37 production from PBMC entailed significant protection from MS relapses. In addition, the in vivo part of the study showed that IL37 was selectively augmented in the sera of MS patients during a relapse and that treatment with the high potency disease-modifying drug fingolimod significantly increased the frequency of patients with circulating blood levels of IL37 (6/9, 66%) as compared to patients receiving no treatment (n = 48) or platform therapy (n = 59) who had levels of IL37 below the limit of the sensitivity of the assay. This finding therefore anticipates that fingolimod may at least partially exert its beneficial effects in MS by upregulating the production of IL37.

Highlights

We evaluated in silico expression and circulating levels of IL37 in patients with different forms of the disease and upon treatment with different disease modifying drugs [37]
We found no difference in the expression levels of IL37 and of the receptors, SIGIRR and IL18R1, when comparing CD4+ T cells from multiple sclerosis (MS) and healthy controls, both in basal and stimulated conditions (Figure 1)
Superimposable reduction in SIGIRR levels was observed in T helper cells, both from

Summary

Introduction

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by demyelination and neurodegeneration [1], which represents the most frequent neuroinflammatory disease in young adults, with a mean age of diagnosis of about 30 years and a worldwide prevalence rate of 30.1 cases per 100,000 population in 2016 [2].Molecules 2020, 25, 20; doi:10.3390/molecules25010020 www.mdpi.com/journal/moleculesWe and others have shown that proinflammatory cytokines such as macrophage migration inhibitory factor (MIF), interleukin (IL), and IL18 can be implicated in progressive forms of the disease [3,4,5,6,7,8] and that an altered balance between proinflammatory Th1 and Th17 cytokines and anti-inflammatory Th2 and Th3 cytokines may represent important pathogenetic events contributing to the onset and clinical course of relapsing remitting forms of the disease, as well as its therapeutic response. Endogenous anti-inflammatory mediators such as IL1-receptor antagonist (IL1-Ra, encoded by the gene IL1RN) [9], soluble IL1-receptor [10], transforming growth factor (TGF)-β [11], and IL4 can be augmented by disease-modifying drugs such as interferon (IFN)-β or glatiramer acetate [12]. Both glatiramer acetate and IFN-β reduce IL17A [13]. A tightly regulated endogenous network composed of proinflammatory and anti-inflammatory cytokines and other cellular and soluble mediators may control the onset and the progression of the disease and may be implicated in its therapeutic response [14]

Methods

Results

Conclusion