BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS), characterized by inflammation and neurodegeneration. The pathophysiology of MS, especially its progressive forms, involves various cellular components, including microglia, the primary resident immune cells of the CNS. This review discusses the role of microglia in neuroinflammation, tissue repair, and neural homeostasis, as well as their involvement in MS and explores potential therapeutic strategies targeting microglial function. METHODS: A literature search conducted in August 2023 and updated in March 2025, using the PubMed database, focused on articles relating to microglia and MS published in 2018-2025. Additionally, ongoing clinical trials of Bruton's tyrosine kinase (BTK) inhibitors were identified through the ClinicalTrials.gov website in November 2023 and updated in March 2025. RESULTS: Microglia are highly adaptive and exhibit various functional states throughout different life stages and play critical roles in neuroinflammation, tissue repair, and neural homeostasis. Their altered activity is a prominent feature of MS, contributing to its pathogenesis. Imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) provide insights into microglial activity in MS. BTK inhibitors and other novel treatments for MS, including masitinib and frexalimab, show promise in modulating microglial function and influencing the disease progression rate. CONCLUSIONS: The multifaceted roles of microglia in CNS development, immune surveillance, and particularly in the pathogenesis of MS highlight the potential of targeting microglial functions in MS treatment. Emerging research on the involvement of microglia in MS pathophysiology offers promising avenues for developing novel therapies, especially for progressive MS, potentially improving patient outcomes in this debilitating disease.

Brain and Mind Center University of Sydney Sydney NSW Australia

Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna Vienna Austria

Danish Multiple Sclerosis Center Department of Neurology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Departamento de Medicina Facultad de Medicina Universidad Complutense de Madrid Madrid Spain

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Neurology Ain Shams University Cairo Egypt

Department of Neurology Hospital Clinico San Carlos IdISSC Madrid Spain

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany

Department of Neurology Medical University of Innsbruck Innsbruck Austria

Department of Neurology Medical University of Vienna Vienna Austria

Department of Neurology Palacky University Olomouc Olomouc Czechia

Department of Neuroscience and Rehabilitation University of Ferrara Ferrara Italy

Division of Clinical Neurosciences University of Turku Turku Finland

Hasselt University Belgium Hasselt Belgium

Laboratory of Experimental Neurology and Neuroimmunology 2nd Department of Neurology AHEPA University Hospital Aristotle University of Thessaloniki Thessaloniki Greece

Multiple Sclerosis Center S Andrea Hospital Department of Human Neuroscience University Sapienza Rome Italy

Neurocenter of Turku University Hospital Turku Finland

Revalidatie and Multiple Sclerosis Noorderhart Pelt Belgium

UNIFE Interdepartmental Center of Research for Multiple Sclerosis and Neuro inflammatory and Degenerative Diseases University of Ferrara Ferrara Italy

Univ Lille Inserm U1172 LilNCog CHU Lille FHU Precise Lille France

University MS Centre Hasselt Pelt Belgium

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