Microglia as therapeutic targets after neurological injury: strategy for cell therapy

ABSTRACT

Introduction

Microglia is the resident tissue macrophages of the central nervous system. Prolonged microglial activation often occurs after traumatic brain injury and is associated with deteriorating neurocognitive outcomes. Resolution of microglial activation is associated with limited tissue loss and improved neurocognitive outcomes. Limiting the prolonged pro-inflammatory response and the associated secondary tissue injury provides the rationale and scientific premise for considering microglia as a therapeutic target.

Areas Covered

In this review, we discuss markers of microglial activation, such as immunophenotype and microglial response to injury, including cytokine/chemokine release, free radical formation, morphology, phagocytosis, and metabolic shifts. We compare the origin and role in neuroinflammation of microglia and monocytes/macrophages. We review potential therapeutic targets to shift microglial polarization. Finally, we review the effect of cell therapy on microglia.

Expert Opinion

Dysregulated microglial activation after neurologic injury, such as traumatic brain injury, can worsen tissue damage and functional outcomes. There are potential targets in microglia to attenuate this activation, such as proteins and molecules that regulate microglia polarization. Cellular therapeutics that limit, but do not eliminate, the inflammatory response have improved outcomes in animal models by reducing pro-inflammatory microglial activation via secondary signaling. These findings have been replicated in early phase clinical trials.

KEYWORDS:

• Microglia
• cell therapy
• neuroinflammation
• traumatic brain injury
• tbi

ARTICLE HIGHLIGHTS

• Neuroinflammation secondary to traumatic brain injury can continue years after initial injury, and it is characterized by persistent microglial activation.

• Microglia have classically been described as having a phenotype that is either pro-inflammatory (M1) or anti-inflammatory (M2). Promoting the M2 response and attenuating the M1 response may increase the likelihood of injury resolution.

• Microglial activation can be observed in positron emission tomography (PET) imaging with radioligands specific for microglial markers.

• In animal models, targeted therapy has shown some success in shifting microglial polarization away from the M1-phenotype and toward the M2-phenotype.

• Therapeutic targets are varied but include molecules or proteins that affect microglial activation and signaling. Examples include enzymes like NADPH oxidase isoform 2 (NOX2) and signal transduction proteins like peroxisome proliferator-activated receptor gamma (PPARγ). Naturally occurring molecules like cyclic AMP (cAMP) and fibrinogen have also been implicated as potential targets.

• Cell therapy has potential in targeting microglia and has already shown to alleviate neuroinflammation secondary to traumatic brain injury (TBI).

Declaration of interest

The authors received funding from Athersys, CBR Systems, Hope Bio, and Biostage. The authors have no other 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.

Additional information

Funding

The authors of this review are funded by National Institute of General Medical Science of the National Institutes of Health (under award number 2T32GM008792).