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

Abstract

Introduction: 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. Areas covered: 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. Expert opinion: 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.

• Authors: Gunnar R Leitner, Tyler J Wenzel, Nick Marshall, Ellen J Gates, Andis Klegeris
• Journal: Expert opinion on therapeutic targets (Expert Opin Ther Targets) Vol. 23 Issue 10 Pg. 865-882 (10 2019) ISSN: 1744-7631 [Electronic] England
• PMID: 31580163 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• TLR4 protein, human
• Toll-Like Receptor 4

Topics

• Animals
• Central Nervous System Diseases (drug therapy, physiopathology)
• Drug Development
• Humans
• Inflammation (drug therapy, physiopathology)
• Molecular Targeted Therapy
• Neurodegenerative Diseases (drug therapy, physiopathology)
• Toll-Like Receptor 4 (agonists, antagonists & inhibitors, metabolism)