Carbon-derived environmental pollutants induce atopic dermatitis-associated skin itch via Artemin

It has been recognized that various organic [carbon-derived] pollutants activate the transcription factor AhR (aryl hydrocarbon receptor). AhR initiate the expression of genes encoding detoxification enzymes in response to xenobiotics (foreign chemicals, not ordinarily found in the body). Such response, if overwhelmed, could lead to pathology. As an example, studies have revealed a relationship between air pollution and the prevalence and exacerbation of atopic dermatitis (AD), a chronic, itchy skin inflammation. 

New study in Nature Immunology showed that AhR signaling in response to organic pollutants initiates skin itch by producing neurotrophic factor, Artemin.

Initially the authors created mice that would constitutively express Ahr in skin epithelial cells (AhR-CA mice). These mice developed more itchy skin and their skin contained more of inflammatory cytokines and cells.

In addition, skin of Ahr-CA mice contained more abundant network of neurons associated with itching behavior (TRPV1+ neurons).

The authors found that neurothropic factor Artemin was highly expressed in skin of Ahr-CA mice.

Depletion of Artemin via antibody injection reduced itching behavior and skin epithelial neuronal density.

Finally, mice lacking Ahr in skin epithelial cells (approximately 70% efficiency for the deletion of Ahr specifically in the epidermis) expressed reduced level of Artemin and display less skin inflammation in response to organic pollutants (though skin-specific Artemin deficiency would have been more valuable here).

In summary, this study suggests that air pollution by carbon derivatives, such as diesel exhaust particles, could initiate manifestation of atopic dermatitis by hyper-activation of the skin Ahr function.

David Usharauli

Part of AIRE KO phenotype (APECED in humans) is dictated by gamma-delta T Cells

AIRE deficiency in mice (human equivalent of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, APECED) leads to chronic tissue immunopathology. Due to role of AIRE in generation of thymic FOXP3+ T regulatory cells, it is believed that underlying cause for tissue pathology on AIRE KO background is a lack of Tregs specific for tissue specific antigens.

However, the new data in journal Immunity from the research group which pioneered the study of AIRE suggest that part of AIRE KO phenotype is dictated by changes in γδ T cells secreting cytokine IL-17.

The authors observed that while total γδ T cells numbers were not different WT and AIRE KO littermates, γδ T cells expressing IL-17 were up-regulated in AIRE KO mice.

Interestingly, AIRE KO mice also deficient for γδ T cells (double deficient mice) showed marked resistance to immunopathology to such tissues as eyes and lungs (though other target tissues were still susceptible).

At the cellular level, there was a significant increase in IL-23r-GFP+ γδ T cells (marker for IL-17+ γδ+ T cells) in retinal tissue in AIRE KO mice at early age, even before tissue pathology was apparent. Of note, the fact that IL-17+ γδ+ T cells are present in retinal tissue in WT mice as well points to its role in physiological processes, not just in pathology).

In summary, this study indicates that subset of γδ T cells could play a leading role in initiating certain tissue pathology on AIRE KO background.

It is not clear, however, how changes in γδ T cell compartment relates to changes in Treg compartment on AIRE KO mice. Also, the role of tissue microbiota and its changes in KOs should be considered to fully understand immunopathologies. In this paper the authors provided the answers to neither to these two relevant topics.

David Usharauli