Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders

• Published in: Expert opinion on therapeutic targets Vol. 23; no. 10; p. 865
• Main Authors: Leitner, Gunnar R, Wenzel, Tyler J, Marshall, Nick, Gates, Ellen J, Klegeris, Andis
• Format: Journal Article
• Language: English
• Published: England 03.10.2019
• Subjects: Animals; Central Nervous System Diseases - drug therapy; Central Nervous System Diseases - physiopathology; Drug Development; Humans; Inflammation - drug therapy; Inflammation - physiopathology; Molecular Targeted Therapy; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - physiopathology; Toll-Like Receptor 4 - agonists; Toll-Like Receptor 4 - antagonists & inhibitors; Toll-Like Receptor 4 - metabolism; Alzheimer’s disease; toll-like receptors; neuroinflammation; neurodegeneration; cytokines; astrocytes; MyD88; microglia; Parkinson’s disease
• ISSN: 1744-7631
• DOI: 10.1080/14728222.2019.1676416

: Adverse immune activation contributes to many central nervous system (CNS) disorders. All main CNS cell types express toll-like receptor 4 (TLR 4). This receptor is critical for a myriad of immune functions such as cytokine secretion and phagocytic activity of microglia; however, imbalances in TLR 4 activation can contribute to the progression of neurodegenerative diseases. : We considered available evidence implicating TLR 4 activation in the following CNS pathologies: Alzheimer's disease, Parkinson's disease, ischemic stroke, traumatic brain injury, multiple sclerosis, multiple systems atrophy, and Huntington's disease. We reviewed studies reporting effects of TLR 4-specific antagonists and agonists in models of peripheral and CNS diseases from the perspective of possible future use of TLR 4 ligands in CNS disorders. : TLR 4-specific antagonists could suppress neuroinflammation by reducing overproduction of inflammatory mediators; however, they may interfere with protein clearance mechanisms and myelination. Agonists that specifically activate myeloid differentiation primary-response protein 88 (MyD88)-independent pathway of TLR 4 signaling could facilitate beneficial glial phagocytic activity with limited activity as inducers of proinflammatory mediators. Deciphering the disease stage-specific involvement of TLR 4 in CNS pathologies is crucial for the future clinical development of TLR 4 agonists and antagonists.