Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and CNS inflammation via the aryl hydrocarbon receptor

By Veit Rothhammer, I. Mascanfroni, L. Bunse, M. Takenaka, Jessica E. Kenison, L. Mayo, C. Chao, B. Patel, Raymond Yan, M. Blain and 12 more. Nature Medicine, 2016

1,114 citations recorded by the source corpus.

Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.

Subfields: Biological Psychiatry, Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/ea676bab3cef9b4315b5900f12771ab7a6bb8b86

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Citations in the corpus

Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. (2018, background): “In an encephalomyelitis mouse model, supplementation with Trp or Trp-derived AhR agonists has been shown to potentiate IFN suppressive effects in an AhR-dependent manner and to limit CNS inflammation (Rothhammer et al., 2016).”
Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis (2019, background): “to pathogenic challenges, and this potential interplay may also influence biological performance of CNS [41].”
Astrocyte crosstalk in CNS inflammation (2020, background): “…by its agonists, AHR can limit NF-κB signaling through several mechanisms including those mediated by the suppressor of cytokine signaling 2 (SOCS2) (Rothhammer et al., 2016; Yeste et al., 2016), and also AHR direct dimerization with the NF-κB subunits RelA and RelB (Rothhammer and Quintana, 2019;…”
Understanding the Holobiont: How microbial metabolites affect human health and shape the immune system (2017, background): “…Candida albicans; exacerbated DSS-induced colitis; and even altered susceptibility to experimental autoimmune encephalomyelitis (EAE) (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012; Rothhammer et al., 2016; Shi et al., 2007; Veldhoen et al., 2008; Zelante et al., 2013).”
Kynurenine pathway metabolism and the microbiota‐gut‐brain axis (2017, background): “…that astrocyte activity and CNS inflammation is modulated by Type I interferons and tryptophan metabolites, via the aryl hydrocarbon receptor (Rothhammer et al., 2016) and administration of a aryl hydrocarbon receptor agonist attenuates intestinal inflammation in a preclinical mouse model of…”
Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain. (2019, background): “Furthermore, kynurenine is an Ah-ligand: a receptor that could play vital roles in neuroinflammatory processes, as well as neuropsychiatric disorders (14, 77).”