Multiple sclerosis: transport channel discovered that blocks inflammation

A study recently demonstrated the key role of the cystine/glutamate amino acid-transporting channel in the function of regulatory T cells (Treg) that block inflammation. Alterations in this transport pathway underlie the reduced growth of these cells in multiple sclerosis (MS).

The study, funded primarily by the Italian Multiple Sclerosis Foundation (IMF), the Ministry of University and Research (MUR) and the Ministry of Health, was published in the prestigious scientific journal Immunity (Cell Press).The research was coordinated by Professor Giuseppe Matarese of the Department of Molecular Medicine and Medical Biotechnology at the University of Naples Federico II, together with Dr. Paola de Candia of IRCCS MultiMedica in Milan and Dr. Claudio Procaccini of the Institute for Endocrinology and Experimental Oncology of the National Research Council (IEOS-CNR) in Naples.

The research team showed that the growth and function of regulatory T cells (Treg), the cells that act as sentinels for maintaining "immune tolerance" and blocking inflammation, depends on the ability to produce a protein, called SLC7A11, a "transport channel" on the Treg membrane that allows the entry of the amino acid cystine and the exit of glutamate. The transport of this amino acid in Treg regulates the balance of free radicals, which are detrimental to the function and growth of these same cells.

The researchers found that Treg cells in multiple sclerosis (MS) patients lost the ability to produce sufficient amounts of SLC7A11 and thus defend themselves against excess free radicals, resulting in their inability to grow and maintain "immunological tolerance" to myelin in the central nervous system, a condition typical of MS.

The study also suggested that SLC7A11 production may be enhanced by conditions of reduced caloric intake (calorie restriction), capable of reducing the "metabolic overwork" of the cell present in overweight and obesity conditions, which are associated with a worse course of MS.

Finally, research has shown that Treg cells from MS patients can recover the ability to produce SLC7A11 after therapy with a first-line MS drug, "dimethyl fumarate-DMF," which would consequently also allow their growth capacity to be restored."No one knows why or for what metabolic defect the Tregs lose their growth capacity and function in MS," - explains study coordinator Professor Giuseppe Matarese - but"DMF would appear to mediate a 'mimetic' action of a state of 'calorie restriction (RC)' (defined as pseudo-starvation), and thus these results would have therapeutic consequences, identifying SLC7A11 as a potential new target for a more targeted 'immunometabolic' therapy of MS."

These implications are indeed already being examined in a larger FISM-funded clinical trial that aims to evaluate the anti-inflammatory effects of an MS therapeutic approach by combining calorie restriction with classical first-line therapies, to assess the ability of diet to enhance the therapeutic efficacy of MS drugs.

The work involves, among others, neurologists such as Professor Diego Centonze of the University of Rome Tor Vergata and IRCCS - Neuromed, Professor Marco Salvetti of the Sapienza University of Rome, Professor Antonio Uccelli of IRCCS Policlinico San Martino in Genoa, Professors Vincenzo Brescia Morra and Roberta Lanzillo of the University of Naples Federico II, and Dr. Giorgia Maniscalco of AORN Cardarelli in Naples. Also collaborating on the study were Dr. Dario Di Silvestre and Dr. Pierluigi Mauri of the Institute of Biomedical Technologies of the CNR in Milan (ITB-CNR), Dr. Silvia Garavelli of IEOS-CNR, and Drs. Fortunata Carbone and Claudia Russo of IRCCS - Fondazione Santa Lucia in Rome/IEOS-CNR. Finally, it should be emphasized that the research is the result of an extensive network of collaborations also from other national (the University of Insubria in Varese, the Ri.MED Foundation in Palermo and AORN "Dei Colli" in Naples) and international (University of Tampere and the University of Helsinki, Finland) research institutions.

Reference

Title: Signals of Pseudo-Starvation Unveil the Amino Acid Transporter SLC7A11 as Key Determinant in the Control of Regulatory T Cell Proliferative Potential

Authors: Procaccini C, Garavelli S, Carbone F, Di Silvestre D, La Rocca C, Greco D, Colamatteo A, Lepore MT, Russo C, De Rosa G, Faicchia D, Prattichizzo F, Grossi S, Campomenosi P, Buttari F, Mauri P, Uccelli A, Salvetti M, Brescia Morra V, Vella D, Galgani M, Mottola M, Zuccarelli B, Lanzillo R, Maniscalco GT, Centonze D, de Candia P and Giuseppe Matarese.

Journal: Immunity 2021