It may come as a surprise that the central nervous system (CNS), the brain and spinal cord, hosts its own specialized active immunity.

The brain and spinal cord are hence not totally immune-privileged. The microglial cells (microglia) are the primary cell type within the immunological community of the CNS and fulfill a diverse set of roles associated with CNS homeostasis and immune defense.

Microglia are brain-resident macrophages forming the first active immune barrier in the central nervous system. Microglia are endowed with spectacular plasticity, allowing them to acquire multiple phenotypes and thereby fulfill their numerous functions in health and disease.

Microglia cells are motile, and within their routine comes the constant patrolling and scanning of the CNS microenvironment and the reaction to danger signals.  

Somehow, virtually every physiological state of the brain, basic developmental and physiological processes, appears, in one way or another, to involve this amazing cell type.  

Microglia exhibit widely differing functions depending on the stage of life and area of residence within CNS. In the healthy prenatal CNS, microglia exert lifelong support to neurogenesis and nerve wiring, and synapse pruning. 

In their role as innate immune cells, microglia play their macrophage “act,” sensing danger signals in the brain tissue microenvironment either caused by pathogens or trauma. Like macrophages, they are phagocytotic, antigen-presenting, and display class II HLA-DR antigens on their surface.   

Following years of debate, as regards their true identity, the basic immune cell identity of the microglia was unraveled by their positive immunohistochemistry (IHC)-staining for the macrophage-associated proteins, the allograft inflammatory factor 1 (Iba1/AIF1, HPA049234), the integrin alpha M complement component (ITGAM/CD11, AMAb90911), and the scavenger receptors CD68 (AMAb90874) and CD163 (HPA046404). 

Microglia: the tissue-resident macrophages of the CNS  

Ontogenetically, microglia arise from fetal hematopoietic stem cells in the yolk sac seeding the rudimentary CNS. However, in contrast to any other hematopoietic cell type, microglia show a surprisingly slow renewal rate, uniquely remaining alive and functional for decades.  

As additional proof of the macrophage-lineage identity of microglia, the autoimmune lymphoproliferative syndrome (ALSP) is manifested by a common deficiency in all macrophage lines. 

Despite their ubiquity, microglia are morphologically and functionally diverse. Single-cell RNA-based sequencing of microglia isolated from post-mortal human brain tissue has unveiled functional states of microglia, each categorized by a particular set of protein markers. Moreover, definable classes or subtypes of microglia show a differential distribution between the white and grey matter.  

This phenotypic and functional variability of microglia is critically determined by local cues (cellular and neurochemical microenvironment) and by the local physical interaction of microglia with neurons or astrocytes. One compelling example is the physical interaction between neurons and the purinergic receptor P2Y12R+ (HPA01379) microglia, an occurrence that seems to offer a neuroprotective role.

Microglial and neurodevelopmental disorders  

Microglial cells respond to various stimuli in the CNS resulting in their activation, which may have a beneficial or a detrimental effect.

The activated microglia remove damaged neurons and infectious agents by phagocytosis, therefore being neuroprotective. However, their chronic activation exacerbates neuronal damage through the excessive release of proinflammatory cytokines, chemokines, and other inflammatory mediators which contribute to neuroinflammation and subsequent neurodegeneration in the CNS. 

Microglial activity is intimately related to neurodevelopmental disorders. Any change in the physiological functions of macrophages and microglia can impact neuroinflammatory and neurodegenerative events. Microglial contribution to disease is associated with compromised physiological roles such as synaptic maintenance and plasticity.   

One of the main functions of microglia within the normal and compromised CNS is to actively regulate myelin homeostasis. MS is a disease characterized by demyelination of axons and chronic inflammation. Within the MS brain, there is a distinction in the transcriptional profiles of human microglia. Active myelin destruction, tightly coupled with inflammation and reactive microgliosis, is a basic characteristic of MS and other demyelinating diseases.  

Iron accumulation is another early pathological hallmark of MS, and in MS lesions, microglia show a distinctive upregulation of the mitochondrial iron transporter proteins, including ABCB6 (HP046723) in response to iron deposition. 

Individuals carrying a defunct copy of the colony-stimulating factor receptor CSF-1R (HPA012323) develop ALSP (autoimmune lymphoproliferative syndrome), a rare hereditary neurodegenerative syndrome that couples to white matter degradation with dementia and motor impairment.  

In neuroinflammatory lesions, the activated microglia display a dramatic loss of homeostatic markers (like P2Y12R) and upregulation of phagocytic markers (CD68) and markers associated with oxidative metabolism like NADPH oxidase (NOX1). The small molecule drug minocycline transiently reduces microglia/macrophage activation. Hence minocycline-induced inhibition of microglial activation shows substantial benefit to the MS-afflicted brain in clinical trials. 

Currently, the clinical treatment of MS includes recombinant IFNb-1a, glatiramer acetate, and natalizumab to mainly regulate T- and B-cells. 

Therapeutic strategies 

Various anti-inflammatory drugs have been identified in treating microglia-mediated neuroinflammation in the CNS. However, hurdles in crossing the blood-brain barrier (BBB), expression of metabolic enzymes, presence of efflux pumps, and several other factors prevent the entry of these drugs into the CNS. 

Nanotechnology can improve the delivery of therapeutic drugs across the BBB for treating microglia-mediated neuroinflammation and neurodegeneration enabling new alternatives with significant promises in revolutionizing the field of neurodegenerative disease therapy. 

Readings

Cserép C. et al., Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science 2020; 367(6477): 528-537  

Masuda et al., Microglia Heterogeneity in the Single-Cell Era. Cell Report 2020; 30(5): 1271-1281

Stratoulias V. et al., Microglial subtypes: diversity within the microglial community. EMBO J. 2019; 38(17):e101997 

Wang J. et al., Targeting Microglia and Macrophages: A Potential Treatment Strategy for Multiple Sclerosis. Frontiers in Pharmacology 2019;10 (28)