Inflammation of central nervous system (CNS) is usually associated with trauma and infection. Neuroinflammation occurs in close relation to trauma, infection, and neurodegenerative diseases. Low-level neuroinflammation is considered to have beneficial effects whereas chronic neuroinflammation can be harmful. Innate immune system consisting of pattern-recognition receptors, macrophages, and complement system plays a key role in CNS homeostasis following injury and infection. Here, we discuss how innate immune components can also contribute to neuroinflammation and neurodegeneration.
Neuroinflammation is the mechanism of CNS inflammation that occurs in response to trauma, infections, and/or neurodegenerative diseases. In neuroinflammation, cellular and molecular immune components such as specialised macrophages (microglia), cytokines, complement, and pattern-recognition receptors are the contributing players. These proinflammatory mediators are either produced locally within the CNS or recruited from the peripheral system following disruption of the blood-brain barrier. This in turn leads to the activation of the glial cells, such as microglia and astrocytes. The effect of neuroinflammation is considered neuroprotective when the inflammatory activity is for a shorter period of time whereas chronic neuroinflammation is associated with harmful consequences for the CNS.
Innate immunity is the first line of defence against the invading pathogens. Some of the components of first line of defence include epithelium (skin, gut, and lungs) that acts as a physical barrier and also produces several kinds of antimicrobial enzymes and peptides, namely, lysozyme, defensins, mucin, lectin [
Microglial cells are the specialised resident macrophages of the CNS. The origin of these innate immune cells is debatable but it is now widely believed that they are of myeloid lineage [
There are a variety of receptors expressed on microglia related to the different functions of these cells. Some of the receptors associated with innate immunity are listed in Table
Innate immune receptors on microglia.
Receptor | Functions/comments | References |
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TLR | Pattern-recognition receptors that respond to self (DAMPs) and nonself (PAMPs) activators. Microglia are known to express TLR1-9. TLRs are implicated in neuroinflammation in response to bacterial and viral infections, Alzheimer’s disease, prion diseases, and amyotrophic lateral sclerosis. | [ |
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NLR | Cytoplasmic pattern-recognition receptors. Microglia are known to express NOD2 in response to CNS infection and NALP3 inflammasome in Alzheimer’s disease. | [ |
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Scavenger | Another group of pattern-recognition receptors. The receptors expressed on microglia are Class A, CD36, and RAGE. | [ |
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RLR | RIG-I is a pattern-recognition receptor that is expressed by microglia in response to viral infections. | [ |
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Complement | Complement receptors expressed include CR1, CR3 and CR4. These receptors bind complement proteins and activate complement pathway which is considered to be both beneficial and detrimental depending on the level of activation. | [ |
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Cytokines | Some of the cytokine receptors expressed in microglia are IL-1R, TNFR (responsible for proinflammatory actions of cytokines IL-1 and TNF- |
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TLR: toll-like receptor; DAMP: damage-associated molecular pattern; PAMP: pattern-associated molecular pattern; NLR: NOD-like receptors; NOD: nucleotide-binding and oligomerisation domain; RLR: RIG-like receptors; RIG: retinoic acid-inducible gene; CR: complement receptor; IL: interleukin; TNF: tumour necrosis factor; TGF: transforming growth factor.
TLR 1–9 receptors are known to be expressed by microglial cells (discussed in detail later). NLR form complexes called inflammasomes (for a detailed review see [
Astrocytes are specialised glial cells and the most abundant cells of the CNS. Morphologically, astrocytes are of two types: protoplasmic (found in grey matter) and fibrous (found in white matter). The basic astrocyte morphology resembles that of a star (with multiple processes). Protoplasmic astrocytes have undistinguishable dense processes while fibrous astrocytes have clearly distinguishable processes [
Like microglia, astrocytes have been shown to express innate immune PRR like TLR, NLR, scavenger, complement, and mannose receptors [
TLRsare expressed on microglia, neurons, and astrocytes similar to dendritic cells, B cells, neutrophils, epithelia, and fibroblast [
Schematic diagram showing structure of TLR and NLR family. TLR: toll-like receptor; NLRP: NOD-like receptor containing pyrin domain; NLRC: NOD-like receptor containing NLR-containing caspase activation and recruitment domain; NLRB: NOD-like receptor containing baculovirus inhibitor of apoptosis protein repeat domain; LRR: leucine-rich repeat; TIR: toll/il-1 receptor; PYD: pyrin domain; CARD: caspase activation and recruitment domain; BIR: baculovirus inhibitor of apoptosis protein repeat. The figure shows the structure of a TLR containing a TIR domain present inside nucleus which is involved in signalling pathway and an LRR domain present in the cytoplasm which is involved in pathogen recognition. NLR are intracellular receptors containing a C-terminal LRR domain, a central NACHT domain, and a variable N-terminal domain which can be a PYD, a CARD, or a BIR domain.
It has recently been shown that oligomerisation of TLR4 with myeloid differentiation protein-2 by morphine causes neuroinflammation [
Some of the exogenous and endogenous ligands of TLR are listed in Table
Exogenous and endogenous ligands of toll-like receptors.
Ligand | TLR | Implications/comments | References |
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Lipopolysaccharide | TLR4 | Recognition of Gram (−) bacteria | [ |
Triacylated lipopeptides | TLR1 and TLR2 | Recognition of Gram (−) bacteria and mycobacteria | [ |
Diacylated lipopeptides | TLR2 and TLR6 | Recognition of Gram (+) bacteria and mycoplasma | [ |
Lipoteichoic acid | TLR2 | Recognition of Gram (+) bacteria | [ |
Zymosan | TLR2 | Recognition of fungi | [ |
Double-stranded RNA | TLR3 | Recognition of virus | [ |
Single-stranded RNA | TLR7 and TLR8 | Recognition of virus | [ |
Flagellin | TLR5 | Recognition of Gram (−) bacteria | [ |
Unmethylated CpG DNA | TLR9 | Recognition of bacteria and virus | [ |
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TLR2; |
Neuroinflammation in Alzheimer’s disease | [ |
Mitochondrial DNA | TLR9 | Pathogenesis of myocarditis and heart failure | [ |
Lung surfactant protein-A and -D | TLR4 |
Innate immune component of lung. Act as opsonin and macrophage activator. Physiological implications of excessive activation by TLR is not known | [ |
Tenascin-C | TLR4 | Maintenance and pathogenesis of inflammation in rheumatoid arthritis | [ |
Fibrinogen | TLR4 | Present normally in serum and activation has been implicated in rheumatoid arthritis and atherosclerosis | [ |
Oxidised low-density lipoprotein | TLR4 | Pathogenesis of atherosclerosis | [ |
MicroRNA let-7 | TLR7 | Pathogenesis of neurodegeneration | [ |
Pneumococcal infection leads to innate immune response in brain and this depends on TLR2 and TLR4 [
In mouse model of AD, MyD88 has been found to prevent memory [
Like TLRs, NOD-like receptors (NLRs) also detect PAMPs and DAMPs. NLRs are intracellular receptors thereby monitoring intracellular environment. They consist of a central nucleotide-binding and oligomerisation (NACHT) domain and a C-terminal LRRs. Their N-terminal component may be variable based on which NLRs are further subdivided. It can be caspase activation and recruitment domain (CARD); a pyrin domain (PYD), or baculovirus inhibitor of apoptosis protein repeat (BIR) termed, respectively, as NLRC, NLRP, and NLRB [
Inflammasomes are multiprotein complexes that activate caspase-1, which in turn leads to processing and secretion of proinflammatory cytokines such as IL-1
NLRP3 inflammasome is involved in the innate immune response to A
Scavenger receptors (SRs) are members of PRRs and are transmembrane glycoprotein PRRs [
Microglia express SR and thus bind to A
The complement system comprises of more than 30 proteins in the serum as well as membrane-bound receptors and regulators. The complement system consists of 3 different initiating or activation pathways culminating into a final common lytic pathway, leading to the formation of membrane attack complex (MAC) (Figure
The complement system. Complement regulators are indicated in red. MBL: mannan-binding lectin; MASP: MBL-associated serine protease; C4BP: C4b-binding protein; CR1: complement receptor 1. The complement system consists of 3 initiating pathways: classical pathway, lectin pathway, and alternative pathway. The classical pathway is usually activated by antigen-antibody complexes, the lectin pathway is activated by microbes with MBL-MASP complex, and the alternative pathway is activated spontaneously by hydrolysis of C3 to C3(H2O). All 3 pathways lead to formation of C3 convertase, followed by C5 convertase, ultimately leading to formation of membrane attack complex. In this process, anaphylatoxins C3a and C5a are also released. The complement system is kept in check by a number of regulators.
Complement is produced mainly in the liver and, over the years, it was thought that the brain was an immune-privileged organ due to the presence of blood-brain barrier. Now, it is well known that components of innate immunity like complement are present and even produced within the CNS. Neuronal cells [
Complement has been shown to play a role in adult neurogenesis. Complement receptors C3aR and C5aR are expressed on neural stem cells and reduced neurogenesis is observed in the absence of C3aR signalling [
CNS can be infected by bacteria, virus, fungus, or protozoa. Deficiency of C3 is associated with increased susceptibility to meningococcal and pneumococcal infections [
Viruses have also evolved mechanisms to evade complement system [
Fungal infection like cerebral aspergillosis leads to increased complement production seen in astrocytes, neurons, and oligodendrocytes, especially C1q production by infiltrating macrophages [
Complement activation occurs in TBI and act as mediators of secondary brain injury [
Cerebral ischemia can lead to the activation of the complement cascade leading to inflammation [
A major role for complement is also seen in neurodegenerative diseases like AD. The neuropathology in AD includes loss of neurons, extracellular amyloid plaques, and intracellular neurofibrillary tangles consisting of abnormally phosphorylated tau protein [
An emerging role for complement in MS has become evident recently [
There is evidence for neuroinflammation in PD as well [
Huntington’s disease (HD) is another neurodegenerative disorder and a genetic cause of dementia. It is inherited as an autosomal-dominant trait characterised by abnormal (at least 36) CAG repeats on the coding sequence of
There has been increasing evidence for involvement of complement in schizophrenia. Schizophrenia is a psychiatric illness characterised by thought insertion, thought withdrawal, hallucinations, delusions, and negative symptoms such as apathy, speech problems, and slow cognition. There is an increase in serum levels of classical pathway complement proteins such as C1q, C1, C3, and C4; increased total complement activity (CH50), CR1 levels; and decreased C4BP levels [
A role for innate immunity in inflammation of CNS is being increasingly evidenced. Cells of the CNS such as neurons, astrocytes, and microglia along with pattern recognition receptors, cytokines, chemokines, complement, peripheral immune cells, and signal pathways form the basis for neuroinflammation. Local synthesis of a number of innate immune humoral factors within CNS offers an opportunity for therapeutic intervention. Furthermore, excessive activation of immune system is thought to be destructive to tissues whereas, simultaneously, it opens up possibilities to harness this activation in a controlled manner to obtain desired therapeutic or preventive strategies in CNS diseases. A detailed understanding of the processes and mechanisms involved in the etiopathogenesis of CNS diseases as well as normal functioning of CNS immunity is essential and can pave the way for reducing excessive neuroinflammation and its effects. Modulation of cellular processes, phenotypes, and functions looks increasingly likely to be a way forward in combating CNS disorders.
Amyloid-
Alzheimer’s disease
Baculovirus inhibitor of apoptosis protein repeat
C4b-binding protein
Caspase activation and recruitment domain
Central nervous system
Complement receptor 1-related protein-y
Damage-associated molecular pattern
Dedicator of cytokinesis 8
Herpes simplex virus
Huntington’s disease
Interleukin
Lipopolysaccharide
Mitogen-activated protein kinase
Mannan-binding lectin
MBL-associated serine protease
Myeloid differentiating factor 88
Nuclear factor-
Nucleotide-binding and oligomerisation domain
NOD-like receptors
Neuromelanin
Pathogen-associated molecular pattern
Parkinson’s disease
Pattern-recognition receptor
Pyrin domain
Receptor for advanced glycation endproducts
Scavenger receptor
Class B SR type I
Traumatic brain injury
Toll-like receptors
Tumour necrosis factor
West Nile virus.
PAMPs are conserved sequences or structural fragments on pathogens (nonself) that are recognised by PRRs. Examples of PAMP include bacterial, viral, fungal, and parasitic-derived lipids (lipopolysaccharide, lipoteichoic acid), proteins (flagellin), carbohydrates (mannan, zymosan), and nucleic acids (dsRNA, CpG).
DAMPs are endogenous molecules released from damaged cells (altered self). Examples of DAMP include heat shock proteins, ATP, and uric acid.
Toxoplasmosis is caused by
Sleeping sickness is also known as Human African trypanosomiasis. It is caused by
Cerebral malaria is encephalopathy caused by sequelae of
Neurocysticercosis is an infection of the CNS caused by the tapeworm
ALS is also known as motor neurone disease and Lou Gehrig’s disease. Majority of the cases are idiopathic with however a small percentage (5–10%) being familial. Mutations in genes
Hydatidiform mole is a gestational trophoblastic disease. Trophoblasts are precursors to placental cells. The products of conception will completely or partially comprise of grape-like vesicles or sacs (villous trophoblast). Most pregnancies are not viable with presenting symptom being vaginal bleeding. Early diagnosis can be established by ultrasonography (“snowstorm” appearance).
Muckle-Wells syndrome is an autosomal dominant disease characterised by the presence of intermittent fevers, rashes, sensorineural hearing loss, and amyloidosis. Mutation occurs in gene
Metabolic syndrome refers to a combination of hyperglycemia, obesity, dyslipidaemia, and hypertension.
MicroRNAs are 22 nucleotide RNAs that are noncoding and repress expression of mRNAs.