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Immune Genes Highly Expressed by Microglia: Roles in Physiological and Pathological Conditions in the CNS
Marianne von Euler Chelpin1* and Gerardo Arrevillaga-Boni2
1Department of Psychiatry and Neurochemistry, Gothenburg University, Sweden
2Department of Physiology and Biophysics, University of California Irvine, USA

ABSTRACT
Microglia are the first line of defense in the Central Nervous System (CNS) and plays a central role in maintaining brain homeostasis. Microglia remove damaged neurons and control innate and adaptive immune responses. Additionally, major emergent activities such as influence in cognition and behaviour, have currently were described. Here we examined the database ImmGen (Immunological Genome Project) to determine which mice genes associated with the immune system had the highest expression in microglia. We found that the Colony Stimulating Factor 1 Receptor (CSF1R), Chemokine (C-C motif) Ligand 3 (CCL3), C1q Complex Protein subunits a, b and c (C1q a, b, c), CX3C Chemokine Receptor 1 (CX3CR1), Interleukin 10 receptor alpha subunit (IL-10ra), C-C Chemokine Receptor type 5 (CCR5), Interferon Gamma Receptor 2 (IFNGR2), Interleukin-10 Receptor Beta subunit (IL-10rb), C-C Chemokine Receptor-Like 2 (CCRL2), Chemokine (C-C motif) Ligand 9 (CCL9), Interleukin-4 Receptor Alpha (IL-4ra), Interleukin-1 Alpha (IL-1a), Chemokine (C-C motif) Ligand 4 (CCL4) and Chemokine (C-C motif) Ligand 6 (CCL6) are highly expressed. We provide a summary of the involvement of these molecules in homeostatic conditions and numerous neurological diseases and hope to awaken the interest to further study these genes and the networks they form in the context of the CNS.
KEYWORDS
Activation; Chemokines; Complement system; Cytokines; Microglia; Neurological diseases

Introduction
Microglia are myeloid cells in the brain and compose the mononuclear phagocyte system along with bone-marrow precursors, circulating monocytes and tissue-resident macrophages [1]. Microglia originate from primitive myeloid progenitors in the yolk sac during embryonal development and migrate into the brain through blood vessels between embryonic stages E8.5 and E9.5 [2]. They represent 10-15% of the total brain cell population [3]. Microglia have been described as double-edged swords [4] exerting important activities in the healthy brain such as neuronal surveillance, pruning, neuromodulation and phagocytosis [5,6] but also being one of the major cell types involved in inflammatory responses in the CNS [7]. Several studies indicate that in response to endogenous stimuli, microglia become activated and releases numerous molecules that can either cause neuronal damage or have neuroprotective properties [5,8,9]. Depending on the molecules they release, microglia can be classified into classically activated M1-like microglia and alternatively activated M2-like microglia (Figure 1). M2-like microglia can be further subdivided (in a similar way as for macrophages) into M2a, M2b and M2c phenotypes [10]. During M1 polarization microglia release several pro-inflammatory mediators including Interleukin-1 Beta (IL-1β), IL-1α, Interleukin-6 (IL-6), Interleukin-12 (IL-12), Interleukin-17 (IL-17), Interleukin-18 (IL-18), Interleukin-23 (IL-23), Tumour Necrosis Factor-Alpha (TNF-α) and Interferon Gamma (IFN-), among other proteins (Figure 1). M2-like microglia produce an array of anti-inflammatory cytokines such as Interleukin-10 (IL-10), Interleukin-4 (IL-4), Transforming Growth Factor Beta (TGF-β) and neurotrophic and growth factors such as Brain Derived Neurotrophic Factor (BDNF) and Nerve Grow Factor (NGF) [9].

At physiological conditions, microglia acquires a surveilling phenotype and express multiple proteins (lower left) necessary to maintain brain homeostasis. When stimulated with Lipopolysaccharide (LPS), IFN- and Granulocyte-Macrophage Colony Stimulating-Factor (GM-CSF) microglia become classically activated and acquire an M1-like phenotype characterized by the release of multiple inflammatory factors. The release of these factors by microglia leads to neurotoxicity causing neurological disorders. In the presence of IL-4, IL-10 and Immunoglobulin G (IgG) microglia become alternatively activated with an M2-like phenotype and release multiple anti-inflammatory factors that lead to neuroprotection.
Microglial markers: Homeostasis vs. activation
Microglia, at homeostasis, express surface markers that are also common to other tissue macrophages such as Cluster of Differentiation Molecule 11b (CD11b), F4/80, Fc-gamma Receptor 1 (CD64), Cluster of Differentiation 115 (CD115 or CSF1R), Ionized Calcium-Binding Adapter Molecule 1 (Iba-1) and proto-oncogene tyrosine-protein kinase MER (MerTK) [11]. This feature makes it hard to discriminate microglia from other CNS-resident myeloid populations. However, recently, several gene expression studies have distinguished surface markers and transcription factors exclusively expressed by homeostatic microglia. These include, Sialic Acid-Binding Immunoglobulin-Type Lectin H (Siglec-H), Fc Receptor-like S (Fcrls) and Purinergic Receptor P2y G-Protein Coupled 12 (P2ry12), among other [12,13].

A property of microglia is their rapid activation after a CNS insult which leads to an increase in cell volume, number and cluster formation [14]. Microglia take on an amoeboid shape and exhibit enhanced immunoreactivity for Iba-1 and upregulate the common leukocyte antigen Cluster of Differentiation 45 (CD45) [11]. Activated microglia also express other molecules that are involved in antigen presentation, T cell stimulation and phagocytosis. These include the major Histocompatibility Complex Class II (Mhc-II), Cluster of Differentiation 11c (CD11c, also known as integrain alpha X), Cluster of Differentiation 80 (CD80, B7-1), Cluster of Differentiation 86 (CD86, B7-2), Cluster of Differentiation 40 (CD40), Cluster of Differentiation 163 (CD163) and Cluster of Differentiation 204 (CD204) [15-18] (Figure 2). Recently, Peferoen, et al., using an in vitro microglia model, showed the existence of microglia populations expressing markers that could differentiate their phenotypes. Cluster of differentiation 74 (CD74), CD40, CD86 and C-C Chemokine Receptor Type 7 (CCR7) were found to be specific for M1-like microglia while Mannose Receptor (MR) and C-C Motif Chemokine 22 (CCL22) were specifically expressed by M2-like microglia [19].

In homeostatic conditions and after activation microglia express a large number of proteins specific for each state.

Finally, it is important to mention that a consensus regarding the nomenclature of CNS-resident vs CNS-infiltrating myeloid cells has not yet been established under inflammatory conditions. A better classification and analysis of the different myeloid cells in the inflamed brain might help untangle their functions during pathological conditions.
Immune-gene expression by microglia in health and disease
In healthy conditions, microglia produce large quantities of secreted proteins that interact with their receptors and assemble important communication networks required to keep brain equilibrium. When homeostasis is disrupted by injury, cellular stress or infections, inflammation raises as a key element that contributes to disease progression and the characteristic worsened outcomes in many severe CNS pathologies. In this context, we believe that if the physiological functions of the immune-genes normally expressed by microglia are elucidated, this might lead to the establishment of molecular mechanisms that could explain some of the symptoms in different brain pathologies associated with inflammation.

We examined the first 1264 positions of the gene expression profiles corresponding to microglia (designated as MF.Microglia.CNS) in the ImmGen database [20,21] to determine which immune-related genes had the highest expression in microglia under basal conditions. Based on the results, the genes were classified into four categories.

1. Colony Stimulating Factor 1 Receptor
2. Chemokines and chemokine receptors
3. Interleukins and interleukin receptors and
4. Complement system proteins (Figure 3)

The highest expressed gene in our selection was CSF1R. Among the chemokines and chemokine receptors we found CCL3, CX3CR1, CCR5, CCRL2, CCL9, CCL4 and CCL6 to be highly expressed. The interleukins and interleukin receptors that had the greatest expression scores were IL-10ra, IFNGR2, IL-10rb, IL-4ra and IL-1a. Finally, genes corresponding to subunits of the complement system C1q (C1qa, C1qb and C1qc) were also highly expressed. The interleukins and interleukin receptors that had the greatest expression scores wereIL-10ra, IFNGR2, IL-10rb, IL-4ra and IL-1a. Finally, genes corresponding to subunits of the complement system C1q (C1qa, C1qb and C1qc) were also highly expressed. Together these results indicate that at physiological conditions microglia have a very high expression of immune-related genes, highlighting the importance of the immune system in maintaining brain homeostasis.

The genes were divided into four categories: other cytokine receptors (CSF1R); chemokines and chemokine receptors; interleukins and interleukin receptors and complement system.

A brief description of the functions and roles of these molecules in healthy state and neurological diseases is provided in table 1.

MIP: Macrophage Inflammatory Protein; ARG1: Arginase-1; EAE: Experimental Autoimmune Encephalomyelitis; TREM2: Triggering Receptor Expressed On Myeloid Cells 2; TH: Tyrosine Hydroxilase; Aβ: Amyloid-Beta Peptide; KO: Knock-Out; CD115: Cluster of Differentiation 115; CD68: Cluster of Differentiation 68; α-Syn: Alpha-Synuclein.
Cytokines and their receptors in the CNS
Cytokines are small signalling proteins (6 to 30 kDa) involved in many biological processes including haematopoiesis, embryonic development and immune response [54]. Cytokines play an important role in the normal brain acting as neuromodulators [55], neurotrophic, growth and survival factors and are also involved in the formation of the cellular structure of the CNS during early development [56]. Increased levels of these cytokines are implicated in most of the neuro-inflammatory diseases we know nowadays, where they can either aggravate tissue damage or neutralise injury by controlling inflammation or supporting tissue remodelling [57]. As previously shown, the gene with the highest expression score in our analysis was CSFR1 that is known to be necessary for microglia viability. Microglia are physiologically dependent on CSFR1 signalling and its inhibition resulted in impairment of proliferation [22,23]. According to the ImmGen database, the IL-1a gene had the highest expression score among interleukins in microglia at physiological conditions. It has been suggested that IL-1 is related with the regulation of neuroendocrine systems, particularly the Hypothalamic Pituitary-Adrenal Axis (HPA) and the hypothalamic-pituitary-gonadal axis. It has an involvement in stress-induced modulation of HPA axis activation; behavioural processes and neural plasticity, suggesting that this cytokine is an important mediator of adaptive stress responses as well as stress associated neuropathology and psychopathology [58]. IL-1 has also been implicated in normal memory consolidation [59].

Upon stimulation, microglia release high levels of a vast number of pro-inflammatory factors that can cause extreme neuroimmune responses (Figure 1). Once the injury ceases the levels of inflammation are generally controlled through the release of multiple anti-inflammatory mediators, among them, IL-10 and IL-4 (Figure 1). The binding of these cytokines to their receptors activates numerous anti-inflammatory signalling cascades [60] that control fundamental steps in the immune response such as decreasing cytokine gene expression and down-regulation of Mhc-II [61].

The fact that microglia express both pro and anti-inflammatory receptors at homeostatic conditions highlights their versatility to adopt different phenotypes in response to the cellular milieu.
Chemokines and their receptors in the CNS
Chemokines are “a group of small (8-14 kDa), mostly basic, structurally related cytokines that regulate cell trafficking of various types of leukocytes through interactions with a subset of seven-transmembrane, G protein-coupled receptors” [62]. Chemokines and their receptors play an important role in the movement of mononuclear cells through the body [63]. Under physiological CNS conditions, microglia exhibit continuous movement of their cellular processes in the intact mouse cerebral cortex and brain [64-66].The functional implication of this baseline motility is still unknown; however, studies in mice have revealed that microglial processes make contact with neuronal synapses in vivo, pointing to a possible role of microglial motility in synaptic remodelling and/or function [67]. We can speculate that the high expression of chemokines in microglia could be related to this basal movement. Chemokines have other non-canonical functions including microbial activity, influence on angiogenesis, protein secretion and proliferation [68].

Our results showed that the chemokine receptor with the highest expression was CX3CR1 (also known as fractalkine receptor). CX3CR1 has been implicated in synaptic pruning of microglia in the healthy brain [69] and is regularly used for tracing microglia lineage [70]. It has been implied that signalling of CX3CR1 with its ligand, the Chemokine (C-X3-C motif) Ligand 1 (CX3CL1) regulates microglia phenotype [71]. Another highly expressed chemokine is CCL3, which has been considered a hippocampal neuromodulator capable of regulating mechanisms of synaptic plasticity involved in learning and memory functions [72]. A dysregulation of CCL3 can result in neuro inflammation, for example, there is an increased expression of this chemokine around sclerotic lesions [73,74]. Table 1 presents a description and involvement of the highest expressed chemokines and their receptors in several neurological pathologies such as Multiple Sclerosis, Alzheimer’s Disease, stroke, trauma and other [75,76].
Complement system in the CNS
“The complement system consists of effectors proteins, regulators and receptors that participate in host defence against pathogens” [77]. Complement opsonins such as C1q interact with complement receptors on the surface to promote phagocytosis [78]. In fact, microglia can phagocytose and clear cellular remains from degenerating neurons through C1q-mediated pathways [79]. The complement system may also be useful in removing aggregated toxic proteins related with neurological disorders and hence, have a protective effect [80]. Modifying the expression of C1q can affect CNS development and lead to neuronal hyper excitability, indicating that the complement system has important roles in neuronal pruning [81]. Although beneficial during development, an uncontrolled complement-mediated pruning of synapses could cause behavioural alterations in mouse models of Alzheimer’s disease [50]. Our findings that C1q gene components are highly expressed on microglia agrees with a study by Fonseca, et al., who identified microglia as being the dominant source of C1q in the brain [82]. Likewise, Depboylu et al., found that microglia were the only cells that expressed C1q in the substantia nigra of Parkinson’s disease patients [79]. This information sheds new light into the importance of C1q both in physiological and pathological conditions, making it a worthy candidate for designing therapies against neurological disorders.
Final Remarks
It is now starting to be recognised that the innate immune cells of the CNS have a pivotal significance in maintaining brain homeostasis. In this context, microglia and the inflammatory status in the CNS have a major and tuning role in brain development and functionality. Microglia have been described as double-edged swords [4] and under pathological conditions they play a crucial role in the development and preservation of the neuro-inflammatory response by showing increased proliferation and activation (Figure 1) [83]. In chronic neurodegenerative diseases of the CNS such as Alzheimer’s disease, Parkinson’s disease and prion diseases, microglia assume an activated morphology and express various molecules that are not typically expressed during healthy conditions and are directly related with the symptoms [5]. It is important to mention that the microglial polarization states proposed here are not definitive and are currently being disputed [84]. Rather, this terminology results from research into monocyte and macrophage biology and there is an ongoing debate to find a proper terminology for microglial activation states.

The curated data presented here (obtained from the only one microglia set available in the ImmGen database) can help visualize the impact of microglia in the basal immunological environment present in the CNS and perhaps predict the implications of its disruption in the context of neurological diseases. We believe that once the functions of these genes in the CNS context are elucidated, it will be possible to develop molecular tools to help modulate inflammation and control adverse effects in CNS pathologies.
Acknowledgement
This work benefitted from data assembled by the ImmGen consortium.

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Figures


Figure 1: Representation of the polarization states of microglia.




Figure 2: Microglia markers at homeostasis and after activation.




Figure 3: Schematic representation of the highest expressed immune-genes in microglia.

Tables
TypeOther NameFunctionDisease ModelReferences
CSF1RM-CSFR, CD115Regulates neuronal survival and differentiationInactivating mutations lead to progressive dementiaRegulates the activation and proliferation of microgliaProlonged inhibition resulted in the blockade of microglia proliferation and shift to anti-inflammatory phenotypeImproved performance in memory and behavioral tasks through pharmacological targetingMicroglia in the adult brain are dependent on CSF1R signalingAlzheimer’s Disease[22,23,24]
Chemokines and Receptors
CCL3MIP1-αInflammatory chemokineRegulates migration, proliferation and cytokine expressionMediates accumulation of microgliaInduces inflammation and cognitive failure through Aβ1-40Neuropathic painBrain injuryAlzheimer’s Disease[25-27]
CX3CR1Fractalkine receptor 1Upregulated after peripheral nerve injuryCritical for the initial development of chemotherapy-induced neuropathic painDeletion of CX3CR1 promotes recovery after spinal cord injury, induces changes in microglia function and enhances endogenous repair and neuroplasticityNeuropathic painSpinal Cord Injury[28,29]
CCR5Chemoattractant proteinBlockade of CCR5 downregulates expression and function of M2 markers (ARG1, IL-10) and reduces microglia migrationAblation of CCR5 prevents neuronal injury and microglia activation; protects against spatial learning and memory impairmentCCR5 KO mice had less number of TH+ neurons, larger dopamine depletion, behavioral impairments and microglia activationGlioblastomaHIV-associated brain injuryParkinson’s Disease[30-32]
CCRL2CCRL2 deficiency exacerbates EAE clinical phenotypesCCRL2 deficiency elevated the microglia markers Iba1, CD68 and TREM2Important player in EAE-associated inflammatory reactionsAnti-inflammatory role during chronic phase of EAEMultiple Sclerosis/EAE[33,34]
CCL9MIP1-gPro-inflammatory chemokinePotential involvement in regulation of macrophage and microglia cellsMelatonin inhibits its expression in BV2 cells       Retinal DamageType 2 Diabetes[35,36]
CCL4MIP1-βRelated with cell motilityExpressed by activated microglia after light damageIncrease in CCL4-CCR5signaling in spinal dorsal horn of diabetic monkeys contributes to neuroinflammation[37,38]
CCL6C10Expressed in rat microglia without stimulationMediates the migration of microgliaMediator of cell-cell communication under physiological and pathological conditions of CNSKey role in the recruitment of macrophage lineage cells to the CNSPossible role in the process of inflammatory demyelinationEAE[39,40]
Interleukins and Receptors
IL10RATrend to increased expression in the anterior lumbar spinal cordAmyotrophic Lateral Sclerosis[41]
IFNGR2Polymorphisms in IFNGR2 allele increase susceptibility to schizophreniaTriplication of IFNGR2 increases inflammation and worsened outcome of Down’s SyndromeParanoid SchizophreniaDown’s Syndrome[42,43]
IL10RBUpregulated in the high risk group of Glioblastoma patients with poor survivalUpregulated in the somatosensory cortex and olfactory bulb of neuroserpin mutated miceGlioblastomaNeuroserpinopathy[44,45]
IL4RA      Upregulation on microglia serves to enhance their sensitivity to IL-4 and promote neuroprotective CNS environmentUpregulation is decreased in microglia of aged mice leading to a failure to induce an anti-inflammatory phenotype[46]
IL1Aα-Syn intra-cerebral injection induces an increased expression of IL-1α in striatumUpregulated after brain damageKey mediator of sterile inflammatory responseParkinson’s DiseaseHypoxic-ischemic brain damage[47-49]
Complement System
C1qaC1qbC1qcProtein levels of C1q significantly increased in refractory epilepsy samplesC1q localizes to microglia and dendritesC1q deficiency causes increased synaptic density and seizuresC1q is increased and associated with synapses in Alzheimer’s modelsNecessary for the toxic effects of soluble Aβ oligomers on synapsesSignificantly increased in sclerotic gray matter lesionsC1qa implicated in response to stimulus and stress. Central role in manifestation of schizophrenia and bipolar disorderEpilepsyAlzheimer’s DiseaseMultiple SclerosisSchizophreniaBipolar Disorder[50,51-53]
Table 1: Involvement in neurological diseases of the highest expressed genes by microglia.

Citation: von Euler Chelpin M, Arrevillaga-Boni G (2017) Immune Genes Highly Expressed by Microglia: Roles in Physiological and Pathological Conditions in the CNS. J Brain Neursci 1: 001