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.

KEYWORDS:

• Alzheimer’s disease
• astrocytes
• cytokines
• microglia
• neurodegeneration
• neuroinflammation
• Parkinson’s disease
• MyD88
• toll-like receptors

Article Highlights

• Toll-like receptor (TLR) 4 antagonists could have beneficial effects in those central nervous system (CNS) diseases that are accompanied by neuroinflammation

• TLR4 antagonists could inhibit overproduction of inflammatory mediators and cytotoxins by glia.

• TLR 4 antagonists could have adverse CNS effects by inhibiting phagocytosis by glia, reducing protein clearance and interfering with myelination.

• Selective TLR 4 agonists could be beneficial by upregulating the phagocytic activity of microglia, leading to enhanced clearance of damaged tissue and abnormal protein aggregates associated with several different CNS diseases.

• Significant adverse effects can be caused by TLR 4 agonists inducing secretion of inflammatory mediators and cytotoxins.

• Agonists that selectively activate the TLR 4 downstream myeloid differentiation primary-response protein 88 (MyD88)-independent pathway should be developed and further studied since such agents could increase phagocytic activity of glia without significantly upregulating glial cytokines and cytotoxins.

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Acknowledgment

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by grants from the Jack Brown and Family Alzheimer’s Disease Research Foundation and from the Natural Sciences and Engineering Research Council of Canada.