Microglia and Dendritic Cells as a Source of IL-6 in a Mouse Model of Multiple Sclerosis

---

Violetta S. Gogoleva^1,a*, Quynh Chi Nguyen², and Marina S. Drutskaya¹

¹Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 117997 Moscow, Russia

²Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

Received December 6, 2023; Revised February 1, 2024; Accepted February 6, 2024

---

Multiple sclerosis (MS) is a complex autoimmune disease of central nervous system (CNS) characterized by the myelin sheath destruction and compromised nerve signal transmission. Understanding molecular mechanisms driving MS development is critical due to its early onset, chronic course, and therapeutic approaches based only on symptomatic treatment. Cytokines are known to play a pivotal role in the MS pathogenesis with interleukin-6 (IL-6) being one of the key mediators. This study investigates contribution of IL-6 produced by microglia and dendritic cells to the development of experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of MS. Mice with conditional inactivation of IL-6 in the CX₃CR1⁺ cells, including microglia, or CD11c⁺ dendritic cells, displayed less severe symptoms as compared to their wild-type counterparts. Mice with microglial IL-6 deletion exhibited an elevated proportion of regulatory T cells and reduced percentage of pathogenic IFNγ-producing CD4⁺ T cells, accompanied by the decrease in pro-inflammatory monocytes in the CNS at the peak of EAE. At the same time, deletion of IL-6 from microglia resulted in the increase of CCR6⁺ T cells and GM-CSF-producing T cells. Conversely, mice with IL-6 deficiency in the dendritic cells showed not only the previously described increase in the proportion of regulatory T cells and decrease in the proportion of T_H17 cells, but also reduction in the production of GM-CSF and IFNγ in the secondary lymphoid organs. In summary, IL-6 functions during EAE depend on both the source and localization of immune response: the microglial IL-6 exerts both pathogenic and protective functions specifically in the CNS, whereas the dendritic cell-derived IL-6, in addition to being critically involved in the balance of regulatory T cells and T_H17 cells, may stimulate production of cytokines associated with pathogenic functions of T cells.

---

KEY WORDS: interleukin-6, microglia, dendritic cells, experimental autoimmune encephalomyelitis, multiple sclerosis, mouse models

DOI: 10.1134/S0006297924050109

Publisher’s Note. Pleiades Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

---