The role of microglia in multiple sclerosis: implications for treatment with Bruton's tyrosine kinase inhibitors

Patrick Vermersch¹Laura Airas^2,3Thomas Berger^4,5Florian Deisenhammer⁶Nikolaos Grigoriadis⁷Hans-Peter Hartung^10,8,9Melinda Magyari^11,12Veronica Popescu^13,14,15Carlo Pozzilli¹⁶Maura Pugliatti^17,18Bart Van Wijmeersch^13,14,15Magd Zakaria¹⁹Celia Oreja-Guevara^20,21*

• ¹Univ. Lille, Inserm U1172 LilNCog, CHU Lille, FHU Precise, Lille, Nord-Pas-de-Calais, France
• ²Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland
• ³Neurocenter of Turku University Hospital, Turku, Finland
• ⁴Department of Neurology, Medical University of Vienna, Vienna, Vienna, Austria
• ⁵Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria
• ⁶Department of Neurology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
• ⁷Laboratory of Experimental Neurology and Neuroimmunology, Second Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
• ⁸Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
• ⁹Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
• ¹⁰Department of Neurology, Palacky University Olomouc, Olomouc, Czechia
• ¹¹Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
• ¹²Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
• ¹³University MS Centre, Hasselt-Pelt, Belgium
• ¹⁴Noorderhart, Revalidatie & Multiple Sclerosis (MS), Pelt, Belgium
• ¹⁵Hasselt University Belgium, Hasselt, Belgium
• ¹⁶Multiple Sclerosis Center, S. Andrea Hospital, Department of Human Neuroscience, University Sapienza, Rome, Sicily, Italy
• ¹⁷Department of Neuroscience and Rehabilitation, University Hospital of Ferrara, Ferrara, Emilia-Romagna, Italy
• ¹⁸UNIFE, Interdepartmental Center of Research for Multiple Sclerosis and Neuro-inflammatory and Degenerative Diseases, University of Ferrara, Ferrara, Emilia-Romagna, Italy
• ¹⁹Department of Neurology, Ain Shams University, Cairo, Beni Suef, Egypt
• ²⁰Servicio de Neurología, Hospital Clínico San Carlos, Madrid, Spain
• ²¹Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Asturias, Spain

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.: 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.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.