Microglia-mediated endotoxin tolerance: A protective role of LPS preconditioning in the central nervous system

Endotoxin tolerance (ET) represents a hyporesponsive state of the innate immune system that develops following prior exposure to endotoxins like lipopolysaccharide (LPS), a potent Toll-like receptor 4 (TLR4) agonist. While ET has been extensively studied in peripheral monocytes and macrophages, its implications within the central nervous system (CNS) remain insufficiently understood. As the resident innate immune cells of the CNS, microglia are central to the regulation of neuroinflammation and can either exacerbate or ameliorate neuronal injury depending on their activation state. Emerging evidence indicates that LPS preconditioning induces microglia-mediated ET, a state that attenuates excessive inflammation and preserves CNS homeostasis. In this review, we synthesize current insights into the concept of ET and elucidate the molecular mechanisms underlying microglial reprogramming, focusing on the coordination of signaling pathways, epigenetic modifications, and metabolic shifts that drive the tolerant phenotype. Within the framework of innate immune memory, we compare ET with trained immunity to highlight their distinct context-dependent effects. Evidence from in vitro co-culture systems and in vivo models of acute CNS injury, neurodegenerative disorders, epilepsy, and psychiatric-like behaviors indicates that LPS preconditioning-induced microglia-mediated ET can confer neuroprotection. We will address the paradox of neuroprotection by LPS preconditioning, underscore the translational potential of LPS-derived TLR4 modulators, and propose future directions for harnessing microglia-mediated ET as a therapeutic strategy for CNS diseases.