Modulating the polarization phenotype of microglia – A valuable strategy for central nervous system diseases

doi:10.1016/j.arr.2023.102160

Ageing Research Reviews

Volume 93, January 2024, 102160

https://doi.org/10.1016/j.arr.2023.102160 Get rights and content

Highlights

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Microglia polarization is involved in many pathological processes.
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Microglial polarization is involved in a variety of central nervous system diseases.
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Current means of intervening in microglial polarization are summarized.

Abstract

Central nervous system (CNS) diseases have become one of the leading causes of death in the global population. The pathogenesis of CNS diseases is complicated, so it is important to find the patterns of the disease to improve the treatment strategy. Microglia are considered to be a double-edged sword, playing both harmful and beneficial roles in CNS diseases. Therefore, it is crucial to understand the progression of the disease and the changes in the polar phenotype of microglia to provide guidance in the treatment of CNS diseases. Microglia activation may evolve into different phenotypes: M1 and M2 types. We focused on the roles that M1 and M2 microglia play in regulating intercellular dialogues, pathological reactions and specific diseases in CNS diseases. Importantly, we summarized the strategies used to modulate the polarization phenotype of microglia, including traditional pharmacological modulation, biological therapies, and physical strategies. This review will contribute to the development of potential strategies to modulate microglia polarization phenotypes and provide new alternative therapies for CNS diseases.

Graphical Abstract

Introduction

In recent years, with environmental changes and the increasing stress of human work and life, the incidence of central nervous system (CNS) diseases has been increasing year by year and has become one of the primary causes of death in the global population(Kaji, 2019). CNS diseases have a serious impact on people's lives, and the treatment and prognosis impose a severe burden on families and society. Currently, CNS disorders include diseases at the brain and spinal cord, mainly including cerebrovascular disease, Alzheimer's disease (AD), Parkinson's disease (PD), brain tumours, demyelination, encephalitis, myelitis, demyelination of the spinal cord, etc. The pathogenesis of CNS diseases is complex, and all are multifactorial and dynamic. Given the heavy burden of CNS diseases on the affected individuals and society, a better understanding of the pathophysiological mechanisms of these diseases are urgently needed to facilitate the development of novel therapeutic strategies. Therefore, the search for common characteristics and safe, effective and appropriate modulating therapies in the pathological processes of CNS diseases is of great social value.

Microglia are specialised macrophages of the CNS, originating from the yolk sac and deriving from the mesoderm. They are already present before the angiogenesis of the CNS. Microglia play an important role in the inflammatory, immune and degenerative processes of the CNS. Microglia cannot be regarded as just a certain type of cell in the brain with certain functions, but must be seen as an important concept that determines the way in which the nervous system develops, cell death, disease and trauma, and the regeneration of the nervous system(Moore and Thanos, 1996).

CNS diseases are a complex group of disorders with a wide range of clinical manifestations. Glial cells activated after CNS injury are mainly astrocytes and microglia, and microglia are the first cell type to respond after CNS injury. Microglia are multi-touch and plastic cells, which are intrinsic immune effector cells in the CNS and play an important role in the synaptic processes of the CNS. Microglia are multifunctional cells that interact with numerous other cells in the CNS, including neurons, astrocytes, and oligodendrocytes(Prinz et al., 2019). Considering these findings, the research on microglia phenotypic transition and microglia-cell interactions is crucial for understanding the pathophysiology of the CNS.

Depending on the degree of activation, the type of stimulation and the local factors present, microglia activation may evolve into different phenotypes: M1 and M2, either contributing to the body's defence and repair, or exacerbating CNS damage. Current research suggests that microglia polarisation plays a critical role in CNS disease. If properly regulated, microglia may contribute to the body's ability to process stress signals in the damaged CNS. Hence, the balance and transition between microglia phenotypes at specific times and in specific patients may be significant in regulating the progression of CNS diseases, with significant clinical therapeutic and research implications.

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Section snippets

Microglia in the healthy state

Microglia are a type of neuroglia, known as the macrophages of the brain and spinal cord. The number and proportion of microglia in the brain varies between species.In normal human brain, the distribution of microglia varies by up to one order of magnitude. The number of microglia accounts for approximately 0.5–16.6% of all brain cells(Ma et al., 2017). The origin of microglia is controversial, with current research showing that microglia are derived from primitive embryonic progenitor cells

Cross talks between polarised microglia and other cells

Microglia can interact with principal cells of the CNS and immune system that are involved in the regulation of the body (Fig. 2). The principal cells of the CNS consists primarily of neurons and glial cells, and alterations in neuron-microglia communication can lead to CNS disease states and associated complications. There are direct and or indirect bidirectional interactions between microglia and neurons, and this interaction occurs in different forms of neuroimmune communication in health

Advances in research to intervene in microglial cell polarization

The different polarization phenotypes of microglia lead to a dual regulatory role of microglia in the same disease. The different polarization phenotypes of microglia are essential for the development of CNS disease injury and neurological recovery. Previous studies have found that artificial induction of M1 type microglia into M2 type microglia reduces CNS disease symptoms and promotes neurological recovery. Therefore, the methods of pharmaceutical, dietary and physical approaches to

Overall conclusion and outlook

The incidence of CNS diseases is increasing year by year and is seriously affecting people's lives. Microglia are the ‘macrophages’ of the brain and play an important role in CNS disease. A variety of factors, including age, gender, diet and disease, can affect microglia polarisation. After activation, microglia may evolve into different phenotypes: M1 and M2. Based on the fact that different microglia phenotypes exhibit different effects in the cellular dialogue, pathological responses, and

Funding Statement

This work was supported by Chengdu University of Traditional Chinese Medicine Youth Foundation Advanced Talents Project (Number: QJJJ2022014). Chengdu University of Traditional Chinese Medicine Rural Revitalization Project (Number: XCZX2022007). Sichuan Natural Science Foundation (Number: 2022NSFSC1406).

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgments

The author would like to thank Biorender for creating custom scientific figures (https://biorender.com/).

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Microglia activation-mediated neuroinflammation after cerebral ischemia is the critical factor aggravating injury of nerve fibers (Kaiser et al., 2019). Specifically, M1 microglia secretes pro-inflammatory factors and neurotoxic substances to promote neuroinflammation and nerve fibers injury, while the M2 phenotype microglia is thought to prevent neuroinflammation and protect nerve fibers by releasing neurotrophic factors (Long et al., 2024). In this research, we found AS treatment decreased the level of M1 markers like CD16, CD86, iNOS and pro-inflammatory factors IL-1β and IL-6.
Astragaloside IV (AS), a key active ingredient obtained from Chinese herb Astragalus mongholicus Bunge, exerts potent neuroprotective and anti-inflammatory effects for treating neurodegenerative diseases. However, mechanisms of AS on improvement of ischemic brain tissue repair remain unclear.
This research aims at using magnetic resonance imaging (MRI) to noninvasively determine whether AS facilitates brain tissue repair, and investigating whether AS exerts brain remodeling through adenosine monophosphate-activated protein kinase (AMPK) metabolic signaling regulating key glycolytic enzymes and energy transporters, thereby impacting microglia polarization.
Ischemic stroke model in male Sprague–Dawley rats were induced through permanent occlusion of the middle cerebral artery (MCAO). Infarct volume, the alterations of brain microstructure and nerve fibers reorganization were examined by multi-parametric MRI. The pathological damages of myelinated axons and microglia polarization surrounding infarct tissue were detected using pathological techniques. Furthermore, M1/M2 microglia polarization associated protein, glycolytic rate-limiting enzymes, energy transporters and AMPK/mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α) signal were examined both in ischemic stroke rats and BV2 microglia treated with lipopolysaccharide (LPS) + interferon-γ (IFN-γ) by western blotting.
MRI revealed that AS obviously decreased infarct volume, relieved brain microstructure damage and improved nerve fibers reorganization in ischemic stroke rats. Histological tests supported MRI findings. Notably, AS promoted microglia M2 and reduced M1 polarization, induced the AMPK activation accompanied with decreased levels of phosphorylated mTOR and HIF-1α. Moreover, AS suppressed the expression of glycolytic rate-limiting enzymes and energy transporters in ischemic stroke rats and BV2 microglia. In contrast, these beneficial effects were greatly blocked by AMPK inhibitor compound C.
Overall, these results collectively suggested that AS facilitated tissue remodeling that may be partially through modulating polarization of microglia in AMPK- dependent metabolic pathways after ischemic stroke.
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Microglia in the healthy state

Cross talks between polarised microglia and other cells

Mol. Cell Neurosci.

Neuron

Arch. Biochem Biophys.

Trends Endocrinol. Metab.

Behav. Brain Res.

J. Neuroinflamm.

Brain Behav. Immun.

Neurobiol. Aging

Neuron

Mol. Neurodegener.

Acta Biomater.

Biomaterials

Neuroscience

Neurotherapeutics

Neuroscience

Brain Behav. Immun.

Exp. Neurol.

Eur. J. Pharmacol.

Exp. Neurol.

Int Immunopharmacol.

Int. J. Cerebrovasc. Dis.

Exp. Neurol.

Brain Res.

Pharm. Res.

Chin. Med

Prog. Neurobiol.

Semin Cell Dev. Biol.

Prog. Neurobiol.

Cell

Cell

Neuroscience

Epilepsia

Stem Cell Rev. Rep.

Int J. Biol. Sci.

Mol. Psychiatry

Cell Death Dis.

J. Spinal Surg.

J. Neuroinflamm.

Front Cell Infect. Microbiol

Neural Plast.

Curr. Neuropharmacol.

Bioeng. Transl. Med.

J. Gannan Med. Coll.

Acta Neuropathol.

Proc. Natl. Acad. Sci. USA

J. Neuroinflamm.

Front. Immunol.

Brain Pathol.

BMC Neurosci.

Int. J. Anesthesiol. Resusc.