Emerging Insights into the Role of Macrophages in Multiple Sclerosis: Pathogenesis and Potential Therapeutic Strategies

Jundong Yang,1,* Ziyue Fu,2,* Qiyuan Zou,3 Zhaoyinqian Li,4– 6 Yuhan Xing1,7 1School of Public Health (Shenzhen), Sun Yat-Sen University, Shenzhen, Guangdong Province, 518107, People’s Republic of China; 2Clinical Medical College, Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China; 3Department of Otorhinolaryngology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Laboratory Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China; 5Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Luzhou, Sichuan Province, People’s Republic of China; 6Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, Sichuan Province, People’s Republic of China; 7Department of Paediatrics, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuhan Xing, School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong Province, 518107, People’s Republic of China, Email [email protected] Zhaoyinqian Li, Department of Laboratory Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China, Email [email protected]: Multiple sclerosis (MS) is a chronic, autoimmune, demyelinating disease of the central nervous system (CNS) in which macrophages play a pivotal and multifaceted role. These highly plastic immune cells are key effectors in the immunopathology of MS, contributing to both inflammatory-driven demyelination and subsequent tissue repair. Historically, macrophage function was viewed through the binary lens of pro-inflammatory M1 and anti-inflammatory M2 polarization. However, recent research reveals a far more complex spectrum of activation states within the dynamic microenvironment of MS lesions. Understanding the intricate signals and molecular pathways that govern macrophage polarization in the CNS represents a critical frontier for therapeutic innovation. Interventions aimed at rebalancing macrophage phenotypes have yielded encouraging results in preclinical models, and some therapeutic agents are now advancing into clinical trials. Future investigations are focused on the diverse functions of macrophages in MS pathogenesis, including their involvement in oxidative stress, antigen presentation, and myelin debris clearance. A particularly innovative approach involves harnessing macrophages as cellular vehicles for targeted drug delivery across the blood-brain barrier, offering a potential solution to one of the most significant challenges in CNS therapeutics. The primary challenge now lies in the safe and effective clinical translation of these macrophage-centered therapies. Successfully navigating this transition from bench to bedside holds the potential to deliver transformative treatments that can halt disease progression and restore neurological function for individuals living with this debilitating disease.Keywords: multiple sclerosis, macrophage, central nervous system, therapy