Journal of Brain & Neuroscience Research Category: Clinical Type: Research Article
Immune Genes Highly Expressed by Microglia: Roles in Physiological and Pathological Conditions in the CNS
- Marianne Von Euler Chelpin1*, Gerardo Arrevillaga-Boni2
- 1 Department Of Psychiatry And Neurochemistry, Gothenburg University, Sweden
- 2 Department Of Physiology And Biophysics, University Of California Irvine, United States
*Corresponding Author:Marianne Von Euler Chelpin
Department Of Psychiatry And Neurochemistry, Gothenburg University, Sweden
Received Date: Oct 04, 2017 Accepted Date: Nov 16, 2017 Published Date: Nov 30, 2017
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.
Figure 1: Representation of the polarization states of microglia.
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
A property of microglia is their rapid activation after a CNS insult which leads to an increase in cell volume, number and cluster formation . Microglia take on an amoeboid shape and exhibit enhanced immunoreactivity for Iba-1 and upregulate the common leukocyte antigen Cluster of Differentiation 45 (CD45) . 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 .
Figure 2: Microglia markers at homeostasis and after activation.
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
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)
Figure 3: Schematic representation of the highest expressed immune-genes in microglia.
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.
|Type||Other Name||Function||Disease Model||References|
|CSF1R||M-CSFR, CD115||Regulates 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 signaling||Alzheimer’s Disease||[22,23,24]|
|Chemokines and Receptors|
|CCL3||MIP1-α||Inflammatory chemokineRegulates migration, proliferation and cytokine expressionMediates accumulation of microgliaInduces inflammation and cognitive failure through Aβ1-40||Neuropathic painBrain injuryAlzheimer’s Disease||[25-27]|
|CX3CR1||Fractalkine receptor 1||Upregulated 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 neuroplasticity||Neuropathic painSpinal Cord Injury||[28,29]|
|CCR5||Chemoattractant proteinBlockade of CCR5 downregulates expression and function of M2markers (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 activation||GlioblastomaHIV-associated brain injuryParkinson’s Disease||[30-32]|
|CCRL2||CCRL2 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 EAE||Multiple Sclerosis/EAE||[33,34]|
|CCL9||MIP1-g||Pro-inflammatory chemokinePotential involvement in regulation of macrophage and microglia cellsMelatonin inhibits its expression in BV2 cells||Retinal DamageType 2 Diabetes||[35,36]|
|CCL4||MIP1-β||Related with cell motilityExpressed by activated microglia after light damageIncrease in CCL4-CCR5signaling in spinal dorsal horn of diabetic monkeys contributes to neuroinflammation||[37,38]|
|CCL6||C10||Expressed 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 demyelination||EAE||[39,40]|
|Interleukins and Receptors|
|IL10RA||Trend to increased expression in the anterior lumbar spinal cord||Amyotrophic Lateral Sclerosis|||
|IFNGR2||Polymorphisms in IFNGR2 allele increase susceptibility to schizophreniaTriplication of IFNGR2 increases inflammation and worsened outcome of Down’s Syndrome||Paranoid SchizophreniaDown’s Syndrome||[42,43]|
|IL10RB||Upregulated in the high risk group of Glioblastoma patients with poor survivalUpregulated in the somatosensory cortex and olfactory bulb of neuroserpin mutated mice||GlioblastomaNeuroserpinopathy||[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|||
|IL1A||α-Syn intra-cerebral injection induces an increased expression of IL-1α in striatumUpregulated after brain damageKey mediator of sterile inflammatory response||Parkinson’s DiseaseHypoxic-ischemic brain damage||[47-49]|
|C1qaC1qbC1qc||Protein 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 disorder||EpilepsyAlzheimer’s DiseaseMultiple SclerosisSchizophreniaBipolar Disorder||[50,51-53]|
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
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  that control fundamental steps in the immune response such as decreasing cytokine gene expression and down-regulation of Mhc-II .
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
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  and is regularly used for tracing microglia lineage . It has been implied that signalling of CX3CR1 with its ligand, the Chemokine (C-X3-C motif) Ligand 1 (CX3CL1) regulates microglia phenotype . 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 . 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 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.
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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
Copyright: © 2017 Marianne von Euler Chelpin, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.