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Overview of Microglia: Nogo-A/NgR Signaling in MS: Comparison
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Please note this is a comparison between Version 2 by Beatrix Zheng and Version 1 by Paschalis Theotokis.

Current therapeutics targeting chronic phases of multiple sclerosis (MS) are considerably limited in reversing the neural damage resulting from repeated inflammation and demyelination insults in the multi-focal lesions. This inflammation is propagated by the activation of microglia, the endogenous immune cell aiding in the central nervous system homeostasis. Activated microglia may transition into polarized phenotypes; namely, the classically activated proinflammatory phenotype (previously categorized as M1) and the alternatively activated anti-inflammatory phenotype (previously, M2). These transitional microglial phenotypes are dynamic states, existing as a continuum. Shifting microglial polarization to an anti-inflammatory status may be a potential therapeutic strategy that can be harnessed to limit neuroinflammation and further neurodegeneration in MS. 

  • multiple sclerosis
  • microglia
  • microglial polarization
  • classically activated microglia

1. Introduction

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS), initiated by an autoimmune response causing severe inflammation and demyelination. The heterogeneous nature of the disease can be characterized by varying levels of demyelination, immune cell infiltration and gliosis across multifocal lesions of the CNS (see review [1]). In people living with MS, a significant health burden is observed in young adults, especially in women between the ages of 20 and 40 years, where the chronic phase is accompanied by irreversible neurological dysfunction and disability, detrimental to the individuals’ quality of life [2,3][2][3].
One of the major effectors involved in the pathogenesis of MS is an innate immune resident cell type of the CNS, the microglia. Microglia play a critical role in maintaining healthy CNS homeostasis, including regulation of synaptic development and plasticity, whilst also promoting cell survival by secreting brain-derived neurotrophic factors (BDNF) [4,5,6][4][5][6]. During pathogenic insults, microglial cells monitor the CNS and trigger an inflammatory response in the dysregulated CNS microenvironment, acting as the first line of the immune defense [7].
During an immune-mediated inflammatory cascade event in MS, microglial cells are activated (see review [8]). Through membrane polarization, microglia migrate to lesions and recruit invading peripheral macrophages, which leads to a proinflammatory response [9]. Activated microglia secrete proinflammatory cytokines IL-6, IL-12, IL-18, IL-23, interleukin-1β (IL-1β), tumor necrosis factor (TNF), chemokines CCL2, CCL3, CCL4, CCL5, CCL7 and CCL22 and reactive oxygen species (ROS) which can accelerate neuronal and oligodendrocyte cell death [10] (see review [11]). However, in a commonly used immune model of MS, the experimental autoimmune encephalomyelitis (EAE) model demonstrated remyelination may be achieved within a pathological CNS environment aiding in amelioration of disease progression, if the microglial phenotype is predominantly shifted to the anti-inflammatory alternatively activated state [12]. This alternative activation of microglia, previously designated as an ‘M2′ phenotype, is a type of polarization state in microglia and macrophages that express anti-inflammatory characteristics, compared to the classically activated (previously ‘M1′) phenotype which expresses proinflammatory characteristics [13]. Several studies on Alzheimer’s disease (AD) [14], amyotrophic lateral sclerosis (ALS) [15], Parkinson’s disease (PD) [16], epilepsy [17] and MS [18], reinforced the importance of altered microglial phenotypes during documented anti-inflammatory mechanisms that govern neurorepair, oligodendrocyte remyelination, axonal regeneration and improved cognitive and motor outcomes throughout the course of neurological disease. On the other hand, phagocytic microglia are considered fundamental in facilitating the clearance of cellular and extracellular debris, thereby modifying a vastly inhibitory microenvironment. In this context, timely removal of myelin debris may be critical in allowing oligodendrocyte migration toward demyelinated lesions, highlighting an exciting means of neurotherapeutics to enable endogenous repair through remyelination and axonal remodeling during progressive MS [19].
Nogo-A as a myelin-associated inhibitory factor (MAIF) was observed in demyelinated lesions of progressive MS [20]. The binding of Nogo-A to Nogo receptor 1(NgR1) is the strongest affinity cognate receptor to the Nogo-66 (amino acids1–40) domain of the full-length Nogo-A ligand. In this MAIF receptor union, NgR1 can trigger a downstream molecular cascade of Ras homolog family member A (RhoA) and Rho-associated coiled-coil containing protein kinase 2 (ROCK2), leading to inhibition of neuronal outgrowth and reduced synaptic plasticity [20]. In the last decade, a growing number of studies related to the effect of the Nogo/NgR signaling pathway on microglial cell function throughout various neurological disorders have emerged [12,21,22][12][21][22]. These studies indicated that the Nogo-A/NgR signaling pathway affects microglial cell adhesion, migration, polarization, phagocytosis and interaction with other cells in neuroinflammatory and neurodegenerative diseases. Therefore, the therapeutic mechanisms targeting Nogo-A/NgR signaling could potentially mediate microglial activation states, which may uncover novel interactions to improve neurorepair and brain neurodegeneration.

2. Origin, Development and Microglia Cell Homeostasis

Microglia are the key immune regulators of neurogenesis, accounting for 5–20% of neural cells [23]. They originate from the yolk sac erythromyeloid precursors, which differentiate into yolk sac macrophages, migrating and colonizing the brain during the fourth week of gestation [24,25][24][25]. Experimental validation of this is limited since the exploration of microglia via fate mapping during gestation in humans is causal. However, the identification of the microglial-specific chemokine receptor, CX3CR1 (observed during embryogenesis), has led to the development of the CX3CR1-CreER mouse model, differentiating endogenous microglia from peripherally derived macrophages [26]. Fate mapping of CX3CR1GFP/+ mice has supported this theory with the presence of CD11b+CX3CR1+ primitive myeloid progenitors in the yolk sac at embryonic day 8 (E8) and detected in the brains of transgenic mice as early as E9.5 [27]. The presence of these microglial cells early in the brain parenchyma correlates with neurogenesis [28[28][29],29], suggesting that microglia could play a role in early development through phagocytosis to regulate synaptic pruning and the neural progenitor cell (NPC) population [4,29][4][29]. The role of microglia in regulating the NPC population is essential for the differentiation into neurons, astrocytes and oligodendrocytes in the development of the CNS [29]. In CX3CR1GFP/+ mice, microglia were observed to regulate synapses of retinal ganglion cells at postnatal day 5 through the binding of complement component 3 (C3) and its receptor CR3, expressed by microglia. This was accompanied by increased lysosomal activity observed in this population of microglia in the dorsal lateral geniculate nucleus [30,31][30][31]. Microglia were reported to be identified in cortical proliferative zones, particularly the subventricular zone (SVZ), in rhesus monkeys at E50, where Iba+ (a common marker used to identify activated microglia) microglia demonstrated significant colocalized expression with the proliferating cell nuclear antigen (PCNA) [29]. As development progressed, these microglia were observed to engulf T-box brain protein 2 (Tbr2) and paired box protein (Pax6) expressing NPCs. This is suggested to lead to the reduction of neural progenitor pools during the later stages of neurogenesis, where Iba+ microglia were evenly distributed in the cortex with reduced pools of NPCs [29].
Microglia also secrete neurotrophic factors such as insulin-like growth factor (IGF-1), BDNF and transforming growth factor-beta (TGF-β) to support neuronal differentiation and oligodendrocyte myelination [32,33,34,35][32][33][34][35]. More specifically, observations in early postnatal rats suggest that IL-1β, interferon-gamma (IFN-γ) and IL-6 secretion from microglia promotes neurogenesis of NPCs to promote oligodendrogenesis [36]. Furthermore, the secretion of IGF-1 from these microglia promoted neuroblast migration to the rostral migratory stream from the SVZ to the olfactory bulbs, where adult neurogenesis occurs [36]. Neurotrophic support derived from microglia can also promote the expression of microglial protein such as neuropilin 1 (Nrp1), which has been reported to stimulate the release of platelet-derived growth factor receptor-α (PDGFR-α), a potent activator of enhancing oligodendrocyte precursor cells (OPCs), by potentiating their proliferation rate [37]. Studies suggest that a two-way communication relationship exists between microglia and NPCs during development, with NPCs regulating microglial cell recruitment into the stem cell niche through the release of factors such as vascular endothelial growth factor (VEGF), that in turn promote the activation and proliferation of microglia [38,39][38][39].
Throughout development, the morphology of microglia transitions from an amoeboid shape to an inactive phenotype that exhibits multiple fine processes. This ramified morphology supports their motility within central tissue, governing their homeostatic regulation through a unique interaction with CNS cells and their ontogenic function [40]. The homeostatic responsibility of microglia during development includes detection of alterations in the microenvironment, adequately responding to phagocytose dying cells and clearing residual myelin debris, accumulated protein aggregates and unnecessary synapses contributing to neuroplasticity [30,31,41,42][30][31][41][42].
Microglia maintain the CNS microenvironment independent of peripheral monocytes, largely due to their proliferative and self-renewal capability [43]. Proliferation rates for microglia are dependent on the area of the CNS surveyed and the technique used to assess cell cycle synthesis and mitosis rates [43,44][43][44]. Studies demonstrated that microglia have cell longevity with observed maintenance of constant populations of microglia throughout life [43,45][43][45]. However, some studies have contradicted these suggestions, indicating that while an increased number of microglial cells were observed in aged populations, decreased proliferation rates also existed [46,47][46][47]. Age is a variable that is not considered or can be controlled in many animal models of neurological diseases, and may explain the failures of translating preclinical results into clinical validation studies. Therefore, further studies are required to explain how age-dependent factors can result in microglial dysfunction and reduction in their abilities when devising novel treatments for progressive neurological diseases.
Microglial cell markers implemented to identify their transition during pathogenesis throughout neurological decline are suggested to distinguish endogenous microglia from peripheral monocytes in human tissue studies and animal models (Table 1).
Table 1. Commonly used markers for different states of microglia in multiple sclerosis and specific animal models.
  Markers  
  Homeostatic

Microglia		 Classically

Activated Microglia		 Alternatively

Active Microglia		 Ref
Multiple sclerosis TMEM119

CX3CR1

P2RY12

Iba1 *

CSF1R		 MRP14+ *

TSPO *

MHC II *

CD68+ *

CD74 *

CD40 *

CD86 *

CD80 *		 CD206 *

TREM2

CD163 *

CD309 *

CCL22 *		 [48,49,50,51,52,53,54][48][49][50][51][52][53][54]
Animal models
Models that include adaptive immune mechanisms (e.g., EAE) TMEM119

P2RY12

Iba1 *

CX3CR1

CD11b+/CD45−

CSF1R

CD68−		 CD74 *

CD40 *

CD86 *

CD80 *

iNOS *

TNF *

IL-12 *		 CD206 *

TREM2

FIZZ1 *

CD163 *

Chil3 *

Arginase 1 *		 [53,][53]55,[55]56,[57,58,56][57][58]59[59]
Innate immune toxin models (e.g., Cuprizone, lysolecithin) TSPO *

CD86

iNOS *

MHC II *

CCL2 *

TNF *

CD83

CD14		 CD206 *

Arginase 1 *

TREM2

MRC1		 [60,61,62,60][61]63,[62]64][[63][64]
* Also expressed by macrophages. CCL: CC chemokine ligand. CD: Cluster of differentiation. Chil3: Chitinase-like 3. CSF1R: Colony-stimulating factor 1 receptor. CX3CR1: C-X3-C motif chemokine receptor 1. FIZZ1: Found in inflammatory zone 1. Iba1: Ionized calcium-binding adaptor molecule 1. IL: Interleukin. iNOS: Inducible nitric oxide synthase. MHC II: Major histocompatibility complex. MRC1: Mannose receptor C-type 1. MRP14: Migration inhibitory factor-related protein 14. P2RY12: Purinergic receptor P2Y12. TMEM119: Transmembrane protein 119. TNF: Tumor necrosis factor. TREM2: Triggering receptor expressed on myeloid cells 2. TSPO: Translocator protein.
These include specific cell membrane expression profiles identified in heterogenous populations as CD45− CD11b+, purinergic receptor P2Y (P2RY12) and transmembrane protein 119 (TMEM119) [65,66,67,68][65][66][67][68]. However, recent studies have questioned the robust expression of TMEM119 in a cuprizone mouse model, a toxin-induced demyelination model where consumption of the copper chelator cuprizone leads to oligodendrocyte death (for review see [69]). TMEM119+ cells were decreased during the cuprizone-induced demyelination, whilst CX3CR1+/eGFP cell expression increased, with less than 10% of cells demonstrating colocalization in the corpus callosum [70]. Furthermore, TMEM119 is expressed by follicular dendritic cells in the CNS; thus, its expression may not be a suitable microglial marker when labeling brain parenchymal cells [70]. Additionally, evidence suggests that microglia could lose their TMEM119 expression during the early stages of MS, implying that TMEM119 may be suited to only identify endogenous microglia in homeostatic but not pathological conditions [51]. Studies that assess the polarization of microglia also utilize markers that are expressed by peripheral macrophages, without discriminating between macrophages and microglia. These markers include CD11b+, Iba1+ and markers for specific phenotypes such as CD206 and arginase 1 (alternatively activated) expression and inducible nitric oxide synthase (iNOS; classically activated) (Figure 1) [13,71][13][71]. Thus, further research exploring polarization should utilize more specific microglial markers and incorporate single-cell RNA sequencing data to differentiate between endogenous microglia and peripheral monocytes. This would allow greater insight into the specific roles of microglia and macrophages and their impact during aging in neurodegenerative disease progression such as MS.
Figure 1. The mechanistic activation of classically activated ‘M1′ and alternatively activated ‘M2′ microglia. In the presence of interferon-gamma (IFN-γ) and lipopolysaccharides (LPS), the resting ‘M0′ microglia undergo polarization towards the classically activated ‘M1′ proinflammatory phenotype by activation of the nuclear factor kappa beta (NF-κB)-dependent pathway. In contrast, the IL-4, IL-10 and IL-13 cytokines trigger signal transducer and activator of transcription (STAT)3/STAT6 phosphorylation within the resting microglia, transitioning cells into the alternatively activated phenotype and increasing the translation of anti-inflammatory cytokines. Under proinflammatory conditions, the classically activated ‘M1′ microglia exacerbate neuroinflammation, whilst the alternatively activated ‘M2′ phenotype can promote repair and regeneration. BDNF: Brain-derived neurotrophic factor. Chil3: Chitinase-like protein 3. CSF-1: Macrophage colony-stimulating factor-1. FGF: Fibroblast growth factors. FIZZ: Found in inflammatory zone. GDNF: Glial cell-derived neurotrophic factor. IGF: Insulin-like growth factor. IKK: I kappa β kinase. IRAK: Interleukin-1 receptor-associated kinase 1. JAK: Janus kinase. MHC: Major histocompatibility complex. MYD88: Myeloid differentiation primary response 88. NEMO: Nuclear kappa- β essential modulator. NGF: Nerve growth factor. RIPK1: Receptor-interacting serine/threonine protein kinase 1. TAB: Transforming growth factor β activated kinase 1 and MAP3K7 binding protein 2. TAK1: Transforming growth factor β activated kinase 1. TGF-β: Transforming growth factor β. TLR: Toll-like receptor. TNF: Tumor necrosis factor. TRADD: Tumor necrosis factor receptor type 1-associated DEATH domain protein. TRAF: Tumor necrosis factor receptor-associated factor. TREM2: Triggering receptor expressed on myeloid cells 2. [Illustration created in BioRender.com accessed on 17 October 2022].
This line of investigation was pursued very recently by Absinta and coworkers (2021), who utilized the characteristic paramagnetic rim signatures of progressive MS lesions captured under MRI to define chronic inflammatory demyelinating edges to consist of microglia inflamed in MS (MIMS) through their specific RNA-seq profile [72]. The interrogation of the leading edges incorporating MIMS identified complement 1q (C1q) as a pathogenic driver validated through conditional deletion of this complement fragment during the course of EAE [72]. There exists an increased complexity of this profile with meningeal inflammation, a common hallmark of brain atrophy and progression correlated with CD68+ and HLA class II expression, along with a loss of P2Y2 and TMEM119 expression that can eventually promulgate a synaptopathy and neuronal loss [73]. Moreover, the metabolic profile during cholesterol metabolism of active phagocytic microglia that express TREM2 suggests that disease-associated microglia (DAMs) can regulate mTOR signaling to regulate lipid metabolism [74]. It has been recently demonstrated that TREM2 mutant microglia fail to respond effectively to lipid-rich debris (myelin cholesterol) leading to cholesterol–ester accumulation during chronic conditions of myelin phagocytosis [75]. Therefore, the evidence suggests that metabolic disruption in chronic microglial-dependent phagocytosis of myelin debris can perpetuate the neuroinflammatory state of the brain, leading to overt neurodegeneration.

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