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Environmental Influences in Psoriasis: the Role of the Dioxin Receptor

Abbreviations: AhR=Aryl Hydrocarbon receptor=dioxin receptor

Psoriasis is a chronic inflammatory condition caused by three factors

  • immunological
  • environmental
  • genetic (innate and adapt immunity, skin specific)

 

Environmental factors include: drug, stress, trauma, tobacco and microorganisms
These influences the interactions between T-cells,  dendritic cells and, keratinocytes
and lead to a metabolic, immune or toxic response of the host

AhR (Aryl Hydrocarbon receptor) is also known as dioxin receptor and acts as a sensor of the environment:
-it is an intracellular receptor (in the cytosol)
-upon ligand-binding, it moves to the nucleus to activate DNA transcription with the help of AhR responsive elements goes into the nucleus to activate transcription
-transcripted and expresses genes include AhR, Cyp1A1, Cyp1A2 and  Cyp1B1

Role of Ultraviolet (UV) radiation in AhR pathway activation
UV Radiation induces synthesis of AhR ligands from Tryptophan

Why is the AhR pathway useful ?
-It has a role in maintaining gut and lung to maintain homeostasis..also in the skin for instance in wound healing and in the functioningg of Langerhans cells.

How is AhR affected  in psoriasis ?
-AhR and AhRR (Aryl hydrocarbon receptor repressor) and Cyp1A1 (2 product genes) are down regulated in psoriasis vs normal cells (microarray analysis)
-Transriptome analysis shows similar results: AhR activation down regulates expression of psoriasis relevant genes
-In mice absence of AhR (knockout) increases psoriasis-like skin inflammation (histology shows acanthosis, parakeratosis and increases marking of growth factors (csf1, cxcl1, s100a8, krt10) and increase in the density of neutrophils)
Activating AhR in wild type mice by applying imiquimod decreases psoriasis-like inflammation
-It can be suggested from here that the activation of AhR suppresses the development of psoriasis-like lesions

In which cells does the AhR pathway play a role  ?
-Dendritic and T cells are not involved

AhR in keratinocytes:
-AhR deficiency in keratinocytes exacerbates skin inflammation
The cells could be initially thought to be keratinocytes or fibroblaste, but when culturing murine keratinocytes and knocking out AhR, there is an increase of inflammation factors

Comments
-Sunlight (UV) stimulates AhR ligand production and could be responsible for the beneficial effects seen when individuals with psoriasis go in the sun.
-tobacco smoke extracts stimulates AhR receptor (and have a role to play in photo aging)…how come does it not have a positive effect on clinical lesions ?

Unravelling the environmental component of psoriasis: stimuli transmitted by the Aryl hydrocarbon receptor (AhR) dampen the severity of psoriatic inflammation. Paola Di Meglio (United Kingdom). SY06 – Pathogenesis of Psoriasis – What’s Clinically Relevant? World Congress of Dermatology 2015 –  Vancouver, Canada