The role of MyD88 in the nervous system: Neuronal functions, implications in neurological diseases, and therapeutic potential

Myeloid differentiation primary response 88 (MyD88), a central adaptor protein governing Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling cascades, is increasingly recognized as a pivotal mediator of neuroimmune interactions and neuromodulation. Beyond its canonical immune functions, emerging evidence reveals widespread MyD88 expression throughout the nervous system, where it plays functional roles in both glial populations and neuronal networks. While previous reviews have largely focused on glial mechanisms, recent studies highlight a complex, often overlooked aspect: the dual role of neuronal MyD88 signaling in orchestrating neurodevelopment while paradoxically driving neuroinflammation and synaptic dysregulation. Given the growing interest in innate immunity's involvement in central nervous system (CNS) diseases, a timely synthesis of MyD88 biology-from molecular mechanisms to therapeutic implications-is essential to bridge the fields of immunology and neuroscience. This article provides a comprehensive review of MyD88, synthesizing contemporary insights into its multifaceted regulatory roles in neural homeostasis and pathogenesis. We place particular emphasis on its mechanistic contributions to brain injury, chronic pain, and neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Furthermore, we evaluate innovative therapeutic approaches targeting MyD88-dependent pathways, highlighting recent pharmacotherapeutic advances and their neuroprotective potential. Finally, addressing the limitations of current strategies, we advocate for a new framework focused on developing therapeutics with increased cell selectivity, thereby advancing the precision and translational potential of MyD88-targeted interventions.