tirsdag den 12. november 2019

Photoimmunology and the ME IDO metabolic trap

The sun emits ultraviolet radiation (UVR) with different wavelengths:

  • UVA (320 - 400 nm)
  • UVB (280 - 320 nm)
  • UVC (< 280 nm)

UVR can cause sunburn and increase the risk of skin cancer. UVR is also immunomodulatory and can be beneficial in the case of inflammatory and autoimmune diseases, but UVR can also exacerbate some autoimmune diseases (1, 2).

Chromophores are the parts of a photorecpetor that absorb photons in light (1).

UVB radiation can be absorped by cytosolic tryptophan, which thus function as a chromophore. This results in the formation of tryptophan photoproducts in particular 6-formylindolo[3,2-b]carbazole (FICZ). FICZ binds to aryl hydrocarbon receptor (AhR) and activates downstream signalling pathways, which contribute to UVR-induced immunosupression (1).

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Figur 1 from reference 3. Light dependent synthesis of FICZ. 6-Formylindolo[3,2-b]carbazole (FICZ) is formed by the action of light on tryptophan. FICZ activation of AhR regulates important biological pathways and increases expression of CYP1A1 as a feedback mechanism to induce its own metabolism (3).

AhR activation by FICZ reduces receptor for IgE (FcεRI) and upregulates IDO expression in Langerhans cells (4).

The IDO metabolic trap hypothesis for ME suggests that antigen-presenting cells are driven into a pathological state with increased cytosolic tryptophan. The following decrease in kynurenine products (including FICZ) may disturb the immune system homeostasis (5).

Several ME patients get better in the sun. Is it because sun-induced FICZ moderate the immune system?

1) Bernard, J.J., Gallo, R.L. & Krutmann, J. Photoimmunology: how ultraviolet radiation affects the immune system. Nat Rev Immunol 19, 688–701 (2019) doi:10.1038/s41577-019-0185-9


2) Fritsche et al: Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8851-6. Epub 2007 May 14. https://www.ncbi.nlm.nih.gov/pubmed/17502624

3) Zhang, C., Creech, K.L., Zuercher, W.J. et al. Gram-scale synthesis of FICZ, a photoreactive endogenous ligand of the aryl hydrocarbon receptor. Sci Rep 9, 9982 (2019) doi:10.1038/s41598-019-46374-7 

4) Koch et al: AhR mediates an anti-inflammatory feedback mechanism in human Langerhans cells involving FcεRI and IDO. Allergy. 2017 Nov;72(11):1686-1693. doi: 10.1111/all.13170. Epub 2017 May 10. https://www.ncbi.nlm.nih.gov/pubmed/28376268

5) Efimov et el. The mechanism of substrate inhibition in human indoleamine 2,3 dioxygenase. J Am Chem Soc. 2012 Feb 15;134(6):3034-41. doi: 10.1021/ja208694g. Epub 2012 Feb 2. https://www.ncbi.nlm.nih.gov/pubmed/22299628

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