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

CARD9 modulates gut inflammation via microbiota-specific tryptophan metabolism

In my previous blogpost I discussed new Science paper that showed relationship between autophagy pathway (ATG16L1) and microbiota-secreted product (PSA-OMV) in driving Crohn's disease (CD) risk. 

As it happens frequently in scientific publication, yesterday another prestigious journal Nature Medicine published another study from another research group that showed relationship between Card9 (C-type lectin sensor, also involved in NOD2 signaling) and microbiota-specific tryptophan metabolism in driving inflammatory bowel disease (Crohn’s disease and ulcerative colitis) risk.  

It is known that Card9^−/− mice are more susceptible to colitis. Here, the authors noticed that Card9^−/− mice are slow to recover after dextran sulfate sodium (DSS)-induced colitis (a self-limiting colitis model) and expressed fewer IL-22⁺ cells, a cytokine with well-known beneficial effects on intestinal homeostasis.

Examination of composition of the fecal bacterial microbiota using 16S rDNA sequencing revealed differences between WT and  Card9^−/− mice gut flora.

Interestingly, germ-free mice transplanted with gut flora from Card9^−/− mice were more susceptible to DSS-induced colitis. This indicated that unlike WT microbiota, Card9^−/− mice microbiota failed to provide "healing" signaling to host's gut epithelium.

One mechanism for this "healing" could be the modulation of aryl hydrocarbon receptor (AhR) activation. Tryptophan can be metabolized either by the gut bacteria into indole derivatives (i.e IAA) or by host cells into kynurenine (Kyn) via indoleamine 2,3-dioxygenase 1 (IDO1). Indole derivatives are AHR ligands and promote IL-22. Indeed, WT microbiota, but not Card9^−/− microbiota, promoted AhR ligand production (Of note, exogenous IL-22 could normalize AhR ligand production and colitis susceptibility in Card9−/− mice).

In vitro assay with AhR reporter system confirmed that Card9^−/− microbiota were defective in activation of AhR signaling.  

Furthermore, supplementation with Lactobacilli strains that are able to produce AhR ligands could restore "healing" effect of Card9^−/− microbiota on gut epithelium.

Finally, the authors showed that fecal samples from IBD patients were indeed deficient in promoting AhR signaling via indole products (genotyping confirmed that fecal samples from IBD patients with Card9 risk allele was associated with reduced AHR activation in their in vitro reporter assay). Of note, the authors said that no such association was observed among other major IBD risk alleles, such as NOD2, ATG16L1 and LRRK2.

In summary, this new study suggests that alterations in IBD risk genes modifies microbiota composition that in turn could tip the balance in favor of "non-healing" microbiota resulting in reduced level of "healing"AhR ligands.

David Usharauli