Inflammation is the primary response of the innate immune system to damage and invasion. While an effective first line of defense, the inflammatory response lacks specificity and causes significant bystander damage. Microglia, the resident macrophages of the central nervous system, exist in a deactivated state where they are actively producing anti-inflammatory and neurotrophic factors. They become activated in response to pathogens or tissue damage and promote the inflammatory response (1, 2).
The inflammatory response is initiated through activation of pattern recognition receptors (PRR), such as the Toll-like receptors (TLRs) in response to pathogen or damage associated molecular patterns (see Inflammasome review). Microglia also express purinergic receptors that respond to ATP released by cells in response to injury, ischemia, or death and scavenger receptors that recognize oxidized proteins and lipids from apoptotic cells. Through these receptors microglia are constantly surveying the local environment for infection or injury (1, 2).
Signaling through PRRs initiates activation of the NFκB, AP-1 and IRF signal transduction pathways. Resulting gene expression promotes the inflammatory response. The inflammatory response is amplified through secretion of pro-inflammatory cytokines such as TNFα and IL-1β. Chemokines such as MCP-1 recruit additional cells and genes with antimicrobial activities such as inducible nitric oxide synthase are activated (1, 2).
While inflammation may not initiate neurodegenerative disease, there is evidence that chronic inflammation involving microglia and astrocytes contribute to disease progression. The inflammatory response has been implicated in Alzheimer's disease, Parkinson's disease and MS. Currently, a major question is whether inhibition of the inflammatory response has the ability to reverse or slow the symptoms of disease (1, 2).
Recent work in the field of MS has demonstrated a role for the ER in repression of inflammation in the brain. ERs have previously been implicated in the etiology of MS and females suffering from relapsing-remitting MS outnumber men by about 3 to 1. Now work done by Saijo et al provides a mechanism for suppression of neuroinflammation by ERβ (2).
AD is characterized by memory loss, impaired cognition, and additional behavioral and neuropsychiatric disturbances. Pathology is associated with the presence of extracellular amyloid β (Aβ) plaques composed of aggregated cleaved amyloid precursor protein and intracellular neurofibrillary tangles made up of hyperphosphorylated tau protein (1, 2).
In AD, microglial cells become activated and astrocytes proliferate and increase in size and motility in areas surrounding senile plaques. Microglia express activation markers and proinflammatory mediators such as MHC class II, Cox-2, MCP-1, TNF-α, IL-1β, and IL-6 (1, 2).
While senile plaques containing Aβ are associated with AD pathology, the causal mechanism is not clear. Aβ aggregates have been shown to activate microglia and induce production of inflammatory mediators associated with neuronal death. Inflammatory mediators include nitric oxide, reactive oxygen species, proinflammatory cytokines, chemokines and prostaglandins (1, 2).
Aβ has been shown to activate microglial cells through three different pathways. Aβ sensing through TLR2/4/6 activates the inflammatory response. Aβ is also sensed by the receptor for advanced glycoxidation end-products (RAGE). RAGE has been reported to participate in Aβ clearance. Increased levels of RAGE ligands and receptor activation are associated with elevated risk of AD in patients with type 2 diabetes. Aβ oligomers and fibrils induce lysosomal damage which induces expression of NALP3, a member of the Nod like receptor (NLR) family expressed in glial cells. NLR proteins are a key component of inflammasomes, protein complexes that participate in caspase1 dependent activation of the proinflammatory cytokines IL-1β and IL-18 (1, 2).
While there is clear evidence of the inflammatory response in AD and inflammation contributes to neuronal death, it is unclear how microglia contribute to AD pathology. Depletion of microglia in a mouse model for AD had no effect on amyloid plaque formation or neuronal damage. In another study, treatment with the growth factor M-CSF resulted in an increase in the number of microglial cells and correlated decrease in Aβ and cognitive loss.These conflicting reports highlight the need for further research in this area (1, 2).
MS is an autoimmune disease that is characterized by inflammation, demyelination and axon degeneration in the CNS. In contrast to AD, MS occurs as a result of immune dysfunction, resulting in an autoimmune response to myelin. The most prevalent form of MS is relapsing-remitting MS, in which the disease alternates between periods of inflammation and demyelination, and remission. Ultimately, relapsing-remitting MS progresses to secondary progressive MS in which patients suffer irreversible disease progression (1-3).
MS occurs when T and B lymphocytes recognize the autoantigen, myelin basic protein (MBP), a component of the myelin sheath in neurons, and induce an inflammatory response. Lymphocyes and antibody producing plasma cells infiltrate into the perivascular region of the CNS. Antibodies and complement are observed in the demyelinated lesions; evidence of the inflammatory response. In relapsing-remitting MS, remyelination can occur during times of remission, but is severely impaired, resulting in ultimate axon degeneration and neuronal death (1–3).
In the absence of a clear genetic cause, MS is believed to arise from a combination of genetic and environmental factors. Viral and bacterial infections are thought to be one possible environmental initiator of MS. Molecular mimicry, or pathogen derived antigens that resemble self antigens, may represent one mechanism of MS initiation. For example, the hepatitis B virus (HBV) encodes one protein with an epitope that is structurally similar to MBP. In HBV infection T cells are activated in response to HBV and cross react with MBP (1, 2).
The innate and adaptive immune responses are activated in MS. T cells recognize MBP presented in the context of the major histocompatability complex on the surface of antigen presenting cells (APCs) such as dendritic cells, macrophages and microglia. APCs secrete cytokines and Induce T cells to differentiate into effector cells. APCs and astrocytes express TLRs which are involved in MS, however whether TLR signaling is protective or disease promoting remains unclear (1–3).
IL-6 and TGFβ secretion induces differentiation of naive T cells into retinoic acid receptor-related orphan receptor γt (RORγt) expressing Th17 cells. Th17 cells secrete IL-17 and TNFα, proinflammatory cytokines, and have been implicated in the pathogenesis of MS (see figure Inflammation in Multiple Sclerosis
Back to top ER and inflammation repression
The ER has been implicated in the etiology of relapsing-remitting MS but the exact mechanism has been unclear. Estrogen has been reported to have anti-inflammatory effects in animal models of MS, suggesting that the ER is involved in regulation of the inflammatory response. Signaling through the ER pathway is initiated through binding of 17β-estradiol to either ERα or ERβ. ERα and ERβ are both expressed in the brain at different levels in different regions. The anti-inflammatory effects of synthetic ER ligands have been extensively studied in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Anti-inflammatory mechanisms include repression of proinflammatory mediators including cytokine, chemokines and matrix metalloprotease 9 in dendritic and microglial cells (3, 4).
Saijo et al recently identified synthetic ERβ specific ligands that inhibit transcriptional activation of inflammatory genes in microglia and astrocytes. Treatment of cells with Indazole-Br and Indazole-Cl inhibits the inflammatory response via an ERβ dependent mechanism (3, 4).
The authors looked for naturally occurring steroids that bind ERβ and inhibit the inflammatory response in the same way. The steroid 5-androsten-3b, 17β-diol (ADIOL) can suppress neuroinflamation and is synthesized from the precursor DHEA. 17β -hydroxysteroid dehydrogenase type 14 (HSD17B14) is the enzyme that converts DHEA to ADIOL. Components of this pathway are highly expressed in microglia. HSD17B14 expression is regulated by inflammatory mediators and is responsible for control of the inflammatory response. Inhibition of the HSD17B14 enzyme or ERβ results in an exacerbated inflammatory response, suggesting that this pathway regulates the level and extent of the response (3, 4).
Indazole-Br and Indazole-Cl suppressed production of cytokines by activated microglia and astrocytes, preventing Th17 cell differentiation and activation. Treatment with Indazole-Cl inhibited EAE initiation and reversed disease progression in animals with established disease (3, 4).
The authors provide a mechanism for inhibition of the inflammatory response by ERβ where ADIOL mediates recruitment of C-terminal binding protein (CtBP) repressor complexes to AP-1 bound promoters. AP-1 binds to the promoters of proinflammatory genes and the ERβ-CtBP repressor complex interferes with AP-1 stimulated proinflammatory gene expression (3, 4).
Inflammation plays a significant role in neurodegenerative disease. The examples of AD and MS above suggest that inhibition of the inflammatory response can inhibit disease development and slow, if not reverse, disease progression. The recent discovery of the role of ERβ in regulation of the magnitude and extent of the inflammatory response will aid in the development of MS treatment strategies that specifically exploit this ER mediated anti-inflammatory pathway however, questions remain (3).
Saijo et al find that 17β-estradiol can compete with ADIOL as a ligand for ERβ. This antagonism may explain the higher incidence of relapsing-remitting MS in females. Other studies found that estrogen and synthetic ER ligands have protective effects in animal models. MS patients experience an 80% reduction in relapse rate during pregnancy followed by a postpartum relapse. Similar effects are seen in rheumatoid arthritis in pregnancy, suggesting that this may occur in other autoimmune diseases. How do we reconcile the protective effects of estrogen and the notion that 17β-estradiol may antagonize the anti-inflammatory effects of ADIOL? What are the effects of birth control and environmental estrogens? Inflammation plays a role in many neurodegenerative diseases, including AD, Parkinson's disease, and amyotrophic lateral sclerosis. Does the ADIOL ERβ pathway play a role in these diseases or is this pathway only protective in autoimmune neurodegenerative disease? These hypotheses require further research (3–5).
- Glass, Christopher K., Kaoru Saijo, Beate Winner, Maria Carolina Marchetto, and Fred H. Gage, (2010) Mechanisms Underlying Inflammation in Neurodegeneration. Cell 140, 918-934.
- Amor, S., F. Puentes, D. Baker, and P. van der Valk, (2010) Inflammation in neurodegenerative diseases. Immunology 129, 154-69.
- Saijo, Kaoru, Jana G Collier, Andrew C Li, John A Katzenellenbogen, and Christopher K Glass, (2011) An ADIOL-ER2-CtBP Transrepression Pathway Negatively Regulates Microglia-Mediated Inflammation. Cell 145, 584-595.
- Gosselin, David, and Serge Rivest, (2011) Estrogen Receptor Transrepresses Brain Inflammation. Cell 145, 495-497.
- Gold, Stefan M., and Rhonda R. Voskuhl, (2009) Estrogen treatment in multiple sclerosis. Journal of the Neurological Sciences 286, 99-103.