Maresin-1 promotes neuroprotection and modulates metabolic and inflammatory responses in disease-associated cell types in preclinical models of multiple sclerosis

  • J Biol Chem. 2025 Mar;301(3):108226. doi: 10.1016/j.jbc.2025.108226.
Insha Zahoor  1 ,  Mohammad Nematullah  1 ,  Mohammad Ejaz Ahmed  1 ,  Mena Fatma  1 ,  Mir Sajad  1 ,  Kameshwar Ayasolla  1 ,  Mirela Cerghet  1 ,  Suresh Palaniyandi  2 ,  Veronica Ceci  3 ,  Giulia Carrera  4 ,  Fabio Buttari  5 ,  Diego Centonze  5 ,  Yang Mao-Draayer  6 ,  Ramandeep Rattan  7 ,  Valerio Chiurchiù  3 ,  Shailendra Giri  8
Affiliations
  • 1. Department of Neurology, Henry Ford Health, Detroit, Michigan, USA.
  • 2. Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health, Detroit, Michigan, USA; Department of Physiology, Wayne State University, Detroit, Michigan, USA.
  • 3. Institute of Translational Pharmacology, National Research Council, Rome, Italy; Laboratory of Resolution of Neuroinflammation, IRCCS Santa Lucia Foundation, Rome, Italy.
  • 4. Laboratory of Resolution of Neuroinflammation, IRCCS Santa Lucia Foundation, Rome, Italy.
  • 5. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Unit of Neurology, IRCCS Neuromed, Pozzilli (Is), Italy.
  • 6. Oklahoma Medical Research Foundation, Oklahoma, Farmington Hills, Michigan, USA.
  • 7. Women's Health Services, Henry Ford Health, Detroit, Michigan, USA.
  • 8. Department of Neurology, Henry Ford Health, Detroit, Michigan, USA. Electronic address: [email protected].
PMID: 39864620 DOI: 10.1016/j.jbc.2025.108226
Abstract

Multiple Sclerosis (MS) is a prevalent inflammatory Neurodegenerative Disease in young people, causing neurological abnormalities and impairment. To investigate a novel therapeutic agent for MS, we observed the impact of maresin 1 (MaR1) on disease progression in a well-known, relapsing-remitting Experimental Autoimmune Encephalomyelitis mouse model. Treatment with MaR1 accelerated inflammation resolution, reduced neurological impairment, and delayed disease development by reducing immune cell infiltration (CD4+IL-17+ and CD4+IFNγ+) into the central nervous system. Furthermore, MaR1 administration enhanced IL-10 production, primarily in Macrophages and CD4+ cells. However, neutralizing IL-10 with an anti-IL-10 antibody eliminated the protective impact by MaR1 in relapsing-remitting Experimental Autoimmune Encephalomyelitis model, implying the significance of IL-10 in MaR1 treatment. Metabolism has been recognized as a critical mediator of effector activity in many types of immune cells. In our investigation, MaR1 administration significantly repaired metabolic dysregulation in CD4+ cells, Macrophages, and microglia in EAE mice. Furthermore, MaR1 treatment restored defective efferocytosis in treated Macrophages and microglia. MaR1 also preserved myelin in EAE mice and regulated O4+ oligodendrocyte metabolism by reversing metabolic dysregulation via increased mitochondrial activity and decreased Glycolysis. Overall, in a preclinical MS animal model, MaR1 therapy has anti-inflammatory and neuroprotective properties. It also induced metabolic reprogramming in disease-associated cell types, increased efferocytosis, and maintained myelination. Moreover, our data on patient-derived peripheral blood mononuclear cells substantiated the protective role of MaR1, expanding the therapeutic spectrum of specialized proresolving lipid mediators. Altogether, these findings suggest the potential of MaR1 as a novel therapeutic agent for MS and other autoimmune diseases.

Keywords
DHA; EAE; IL-10; MS; Maresin1; Metabolism; SCENITH; SPM; inflammation; resolution; therapeutics.
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