Microglial control of astrocytes in response to microbial metabolites: AHR participates in CNS inflammation (e.g. multiple sclerosis)

Authors [see attached article] identified positive and negative regulators that mediate the means by which microglia [cells in the glia of brain that function as macrophages (scavengers) in the central nervous system (CNS)] control astrocytes (star-shaped glial cells in the CNS). These exciting results define a pathway through which microbial metabolites [derived from bacteria in the gastrointestinal (GI) tract] limit pathogenic activities of microglia and astrocytes –– thereby resulting in the suppression of CNS inflammation. Authors suggest that this pathway may lead to new therapies for multiple sclerosis and other (inflammatory) neurological disorders.

That darned aryl hydrocarbon receptor (AHR) transcription factor just seems to keep popping up in the middle of every critical-life function. J Microglia in the CNS have been known to express AHR. To investigate the role of microglial AHR on CNS inflammation, authors generated a transgenic mouse in which a tamoxifen-inducible promoter drives expression of Cre recombinase fused to an estrogen ligand-binding domain. After treatment of these mice with tamoxifen, AHR-expressing peripheral cells are replenished from bone marrow –– while microglia remain AHR-deficient without any abnormal cell death. Microglial AHR deletion led to worsened conditions of experimental autoimmune encephalomyelitis (EAE), which led to increasing demyelination and CNS monocyte recruitment; the T-cell response remained unaffected. Collectively, these findings suggest that microglial AHR limits (i.e. is able to suppress) EAE. NF-κB (a protein complex that controls transcription of DNA, cytokine production, and cell survival) controls microglial responses during EAE, and AHR can limit NF-κB activation in a SOCS2-dependent manner (SOCS2 = suppressor of cytokine signaling-2, a key regulator of growth hormone, insulin-like growth factor, and other signaling pathways implicated in inflammation and cancer). Deletion of microglial AHR thus caused decreases in Socs2 expression and resulted in up-regulation of transcripts associated with microglial activation, inflammation, and neurodegeneration.

As previously discussed recently in these GEITP pages, AHR is known to be associated with “reception of environmental, as well as endogenous, signals” –– including the stress signal of inflammation. This resulting in a cascade of downstream events programmed to respond to those incoming signals (in ways to promote cell and organism survival) [recently reviewed in: Progr Lipid Res 2o17; 67: 38]. Below is Table 1 from that review. As can be see, as a member of the bHLH/PAS family, AHR participates in virtually all fundamental/developmental and critical-life functions in the living organism:

Table 1

Summary of organs, systems, cell functions, and developmental biology in which AHR-signaling is involved.

Location AHR-signaling pathway involvement

Central nervous system Development of brain and nervous system; Neurogenesis; Neuronal cell development; Cardiorespiratory brainstem development in ventrolateral medulla; “Brain-gut-microbiome”

Eye Ciliary body formation and function; Thyroid-associated eye disease

Gastrointestinal tract Development of GI tract; Rectal prolapse during aging; “Brain-gut-microbiome”

Heart Development of heart organ; Cardiovascular physiology; Atherogenesis; Cardiomyogenesis; Cardiorespiratory function

Hematological system Development of blood cell-forming system; Hematopoiesis; Activation or suppression of erythroid development

Immune system Immune system development; The immune response; Innate immunity; Pro-inflammatory response; Anti-inflammatory response; Immunomodulatory effects

Inner ear Development of the cochlea

Kidney Development of the kidney; Hypertension

Liver Development of liver organ; Hyperlipidemia; Glucose and lipid metabolism; Hepatic steatosis

Musculoskeletal system Transmesoderm → osteoblast transition; Bone formation; Osteoclastogenesis

Pancreas Development of pancreas; Beta-cell regulation; Pancreatic fibrosis

Endocrine system Serum lowered testosterone levels; Infertility; Mammary gland duct cell epithelial hyperplasia; Degenerative changes in testis; Gerrm-cell apoptosis; Endometriosis

Reproductive system Development of male and female sex organs; Spermatogenesis; Fertility

Respiratory tract Development of respiratory tract; Disruption of GABA-ergic transmission defects; Cardiorespiratory function

Vascular system Angiogenesis; Atherosclerotic plaque formation

Skin Barrier physiology; Atopic dermatitis

Cellular functions Cell migration; Cell adhesion; Circadian rhythmicity

DNA changes DNA synthesis; DNA repair; DNA-adduct formation; Mutagenesis

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