The role of the Toll-like receptor family in stroke: functions, mechanisms and therapeutic targets

Toll-like receptors (TLRs) are pivotal pattern recognition receptors in the innate immune system, primarily responsible for detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). This review comprehensively examines the dual role of TLRs in stroke pathophysiology, wherein they exacerbate inflammatory brain injury yet also harbor neuroprotective potential. We delve into the core signaling mechanisms, specifically the MyD88-dependent and TRIF-dependent pathways, and evaluate their relevance as therapeutic targets. Furthermore, we synthesize emerging insights into novel regulators of TLR activity, including dietary components via the gut-brain axis and exosome-mediated intercellular communication. By integrating evidence from other inflammatory diseases, we propose targeted strategies to balance the detrimental and beneficial effects of TLR activation. The therapeutic potential of TLR agonists, antagonists, and combination therapies is critically appraised. Finally, we delineate future research priorities, including the optimization of TLR modulation, exploration of combination therapies, and cross-disease mechanistic studies, to fully realize the translational promise of TLRs in stroke therapy. • Clinical trial data for TLR-targeted therapies have been added to clarify translational potential. • Causal links between TLR signaling pathways and downstream cellular events are now clarified. • Emerging mechanisms including gut-brain axis, spreading depolarizations, and SNPs are discussed. • Timing of TLR modulation and potential therapeutic risks are addressed for clinical relevance.