Urocanase-Positive Skin-Resident Bacteria Metabolize cis-Urocanic Acid and in Turn Reduce the Immunosuppressive Properties of UVR

Abstract

The skin microbiome plays an important role in health and disease. We have recently shown that microbes living on the skin regulate the immunomodulatory properties of UVR, but the underlying mechanisms remain to be uncovered. Using a preclinical model of immunosuppression against the chemical allergen 2,4-dinitrofluorobenzene, 16S microbiome sequencing, in vitro cultures, high-performance liquid chromatography-mass spectrometry and the generation of gnotobiotic-like mice, we report that acute UVB radiation induces a transient and significant restructuring of bacterial communities on the skin through one of its major photoproducts, cis-urocanic acid. Certain bacteria, such as Staphylococcus epidermidis, use urocanase (HutU) to metabolize cis-urocanic acid to proliferate. This in turn affects the concentration of cis-urocanic acid on the skin, limiting its ability to suppress adaptive immune responses and induce tolerance to 2,4-dinitrofluorobenzene. Interestingly, addition of a topical urocanase inhibitor restricts the metabolism of cis-urocanic acid by HutU+ bacteria and restores immunosuppression. Overall, these results illustrate how, by harnessing a unique nutrient produced in response to UVR, urocanase-positive skin-resident bacteria can fine tune immune responses to environmental antigens. They should open new avenues to enhance the beneficial effects of phototherapy protocols and sun protection.

Keywords: Antigen tolerance; Cis-urocanic acid; Microbial metabolism; Skin microbiome; UVR.