Sunday, June 22, 2014

Aryl Hydrocarbon Receptor senses in[toxic]ated skin environment

Aryl Hydrocarbon Receptor (AhR) sense the presence of xenobiotics (e.g. antibiotics) or toxic environmental pollutants (e.g. dioxin). This process induces activation of liver enzymes, like CYP1A1, necessary for toxin deactivation. AhR's endogenous ligands are dietary-derived indoles and flavonoids. In addition, some high affinity endogenous AhR ligands, like FICZ, are derived from tryptophan metabolism upon UV or visible light exposure.

Many immune-related inflammatory disorders, like allergy, asthma or eczema are thought be exaggerated by environmental pollutants.

I would like to review two recent papers (second review is coming in few days) that address the role of AhR in tissue inflammatory response.

The first paper was published in Immunity and came from Brigitta Stockinger' lab (1).

Her lab is well known for their pioneering work in Th17 subset biology. I actually remember that it was in the summer of 2006 when our Lab Chief came from one of the conference and mentioned that Brigitta Stockinger's lab has identified new T helper subset that required IL-6 and TGF-beta. It was complete unorthodox idea then. That original paper itself was published a little bit later in Immunity.

In this new immunity paper, her lab examined the role of AhR in imiquimod-induced psoriasiform skin inflammation (if interested, I have already reviewed earlier paper from von Andrian's lab about imiquimod-induced psoriasiform skin inflammation).

Imiquimod is a anti-viral topical medicine. It activates TLR7 and also activates, indirectly, nociceptors and IL-23-IL-17 axis.

First, the authors examined effect of AhR agonist, FICZ, on psoriasis-related gene (psoriasis transcriptome) expression using clinical skin biopsies. 70% of psoriasis-related genes (e.g. IFIT1) were reduced after treatment of lesional skin biopsies with FICZ.

To study AhR effect on psoriasiform skin inflammation, the authors used AhR-deficient mouse model. While untreated skins from both AhR +/+ and AhR -/- mice were similar, 5-day application of imiquimod induced greater inflammation and skin thickening in AhR -/- mice. This exaggerated skin inflammatory response was reduced with FICZ. The authors did not show data if any off-target effect exist with FICZ (e.g. treatment of AhR -/- mice with FICZ after imiquimod application).

Next, the authors conducted series of experiment to determine which cell subset required AhR expression to recapitulate clinical observation of AhR -/- mice. There was no difference in skin inflammation when AhR was specifically deleted in CD11c+ cells (Ahr fl/- CD11c-cre mice). Also, Specific deletion of AhR in T and B cells (Ahr fl/- RAG1-cre mice) did not recapitulate clinical observation seen in AhR -/- mice after imiquimod application.

However, bone marrow chimeras in which nonhematopoietic cells were of AhR -/- phenotype but bone marrow cells of wild type could recapitulate total AhR deficiency, but not other way around. This indicated that absence of AhR response in the nonhematopoietic cell subsets contributed to observed exaggerated skin inflammation in AhR-deficient mice after imiquimod application.

The authors further showed that AhR -/- skin cells (keratinocytes) showed hyper responsiveness (greater expression of cxcl1, csf2, csf3) to condition medium derived from imiquimod treated skin samples. This exaggerated response of AhR -/- keratinocytes were primarily driven by IL-1beta, since recombinant IL-1beta could replace condition medium for this effect and neutralization of IL-1beta abrogated keratinocytes hyper response to imiquimod treated skin condition medium.

In summary, this paper showed that AhR expression in keratinocytes is required to dampen skin inflammatory response to IL-1beta during psoriasiform skin reaction. The source of this IL-1beta is not shown here but presumably is derived from hematopoietic cells, like dendritic cells, since its production requires inflammasome activation. While, the authors did not identify the ligands that activate AhR in keratinocytes in imiquimod-induced psoriasiform skin, the fact that sunlight and two light-sensitive vitamins D and A derived medicine (calcipotriol, isotretinoin) has been shown to be effective in psoriasis treatment indicate that AhR ligands represent prospective medical targets.


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