Skin fibroblasts shield mast cells

Extracellular ATP is released in response to cellular stress and serves as a 'danger' signal that can activate immune cells via P2 purinoceptors, such as P2X₇. Previous work has shown that mast cells from the skin and intestine have differential P2X₇ expression but it has been unclear why this is. Kurashima et al. now show that skin fibroblasts inhibit mast cell expression of P2X₇ by producing enzymes that degrade retinoic acid (RA), a vitamin A metabolite. This activity of fibroblasts promotes homeostasis in the skin by limiting mast cell activation.

Credit: NPG

skin fibroblasts limit the expression of P2X₇ by local mast cells

The authors isolated mast cells from various tissues and, in keeping with previous findings, showed that intestinal mast cells express higher levels of P2X₇ compared with mast cells from other tissues. Mast cells from the lungs and peritoneum expressed intermediate levels of P2X₇, whereas skin mast cells showed very low levels of P2X₇ expression. Accordingly, although mast cells from other sites produced pro-inflammatory mediators following stimulation with ATP, skin mast cells did not respond. Experiments in which bone marrow-derived mast cells were transferred into the skin of mast cell-deficient mice indicated that local environmental factors suppress mast cell expression of P2X₇. Studies using germ-free mice or mice deficient in various immune cell populations suggested that this suppression of P2X₇ expression did not depend on the commensal microbiota or on local immune cells. Similarly, inhibition of P2X₇ expression did not require skin-associated immunomodulatory mediators such as interleukin-10, prostaglandin E2 and vitamin D3 metabolites. However, the co-culture of bone marrow-derived mast cells with skin fibroblasts (but not with intestinal fibroblasts) suppressed their expression of P2X₇. This suggests that skin fibroblasts limit the expression of P2X₇ by local mast cells.

To unravel the mechanisms involved, the authors carried out gene microarray analyses. They found that skin fibroblasts expressed higher levels of the RA-degrading enzymes Cyp26a1 and Cyp26b2 compared with intestinal fibroblasts, and that exposure of mast cells to RA promoted their upregulation of P2X₇. Furthermore, the treatment of skin fibroblasts with an inhibitor of CYP26B1 led to increased expression of P2X₇ by co-cultured mast cells. Disruption of retinoid signalling has previously been associated with skin inflammation, so the authors examined whether high doses of RA can disrupt skin homeostasis by upregulating P2X₇ on mast cells. Indeed, mice that were repeatedly administered high doses of RA developed dermatitis, and this skin inflammation was exacerbated if the mice were treated with a CYP26B1 inhibitor. Notably, the RA-induced dermatitis was associated with high concentrations of extracellular ATP in the skin and was ameliorated in mice deficient in P2X₇ or mast cells. The authors found that the skin microbiota also contributes to the development of RA-induced dermatitis; signals from local commensals seem to recruit and activate monocytes and macrophages, and increase their release of ATP and other P2X₇ ligands.

In summary, this study shows the importance of local fibroblasts in maintaining mast cell quiescence and homeostasis in the skin. Of note, previous studies have linked high levels of vitamin A intake with the exacerbation of skin inflammation in humans — these new data offer a possible mechanistic explanation.