Marina Bekić2, Nataša Ilić2, Jelena Đokić1, Dušan Radojević1*, Dragana Vučević3, Saša Vasilev2, and Sergej Tomić2
1Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia
2Institute for the Application of Nuclear Energy, University of Belgrade, Banatska 31b, 11080 Belgrade, Serbia
3Medical Faculty, Military Medical Academy, Defence University, Crnotravska 17, 11000 Belgrade, Serbia
dradojevic [at] imgge.bg.ac.rs
Abstract
Although genetic predisposition to Multiple Sclerosis (MS) may play an essential role in disease development, myeloid cell overactivation and gut microbiota dysbiosis are key contributors to MS pathogenesis. Myeloid-Derived Suppressor Cells (MDSC)s are immature myeloid cells with strong immunosuppressive functions which can be exploited in the treatment of autoimmune diseases. Considering the limited data on MDSCs application in MS therapy and their poorly studied effects on the gut microbiota, we have investigated the therapeutic potential of mice MDSC differentiated according to the standard protocol (MDSC) and modified with the addition of prostaglandin (PG)E2 (MDSC-PGE2) to ameliorate experimental autoimmune encephalomyelitis (EAE) induced with MOG35-55/CFA/PtX in C57BL/6 mice. Additionally, we analyzed the changes in gut microbiota features in control and MDSC-treated animals by using a shotgun metagenomics approach. In mice, PGE2-activated MDSC significantly inhibited the onset and clinical course of EAE. This effect correlated with increased IL-10, TGF-β, IL-4 production, and Arginase-1 level in MDSC-PGE2, as well as with reduced leukocyte infiltrates in the spinal cord. MDSC-PGE2 protective effect is also reflected in the maintenance of gut microbiota composition based on Kraken2/Bracken2 and LEfSe analysis. We observed an increase of MS-associated species Romboutsia ilealis in the control EAE group, while in both MDSC treatments the increase in relative abundances of Muribaculum gordoncarteri and Duncaniella dubiosis, associated with immunoregulatory properties, was observed. Microbial metabolic pathways profiling using Humann3 pipeline also reveals the increase in pathways involved in the production of potentially immunoregulatory metabolites in the MDSC-PGE2 group. In conclusion, we pointed to the significant association between the efficacy of MDSC-PGE2 treatment and gut microbiota features which can be further exploited in order to improve MDSC-based EAE therapy.
Keywords: Myeloid derived suppressor cells, gut microbiota, functional pathways, multiple sclerosis, immunoregulatory mechanisms
Acknowledgement: This research was supported by the Ministry of Science, Technological Development and Innovation of the Republic of Serbia under Contract No. 451-03-47/2023-01/ 200042 and No. 451-03-47/2023-01/200019, and by the Science Fund of the Republic of Serbia, PROMIS, #6062673, Nano-MDSC-Thera.
