1052 Urocanase-positive bacteria in the skin regulate the immunomodulatory properties of the UV photoproduct, cis-urocanic acid

Increasing evidence illustrates that the skin microbiome plays major roles in health and diseases. Recently, we have shown that bacteria living in the skin regulate the immunomodulatory properties of UV radiation. To gain further insight into the underlying mechanisms, we exposed C57BL/6 mice to UVB or topical cis-urocanic acid (cis-UCA), a major UV photoproduct, and examined the ability of skin bacteria to degrade this compound and reduce its immunosuppressive properties in a standard model of contact hypersensitivity (CHS) to 2,4-dinitrofluorobenzene. UV and its mediator cis-UCA induced transient but significant perturbations in skin bacterial communities with increased abundance of several bacterial phylum such as Firmicutes and Proteobacteria. Bioinformatic analysis showed that several of the increased bacteria, such as Staphylococcus epidermidis (S.epi), expressed the HutU gene, which encodes urocanase that degrades urocanic acid. In vitro culture experiments demonstrated that HutU+ but not HutU- strains use cis-UCA for growth, which certainly explains why the amount of cis-UCA produced in the skin after UVB exposure is dramatically increased in mice disinfected with chlorhexidine. Comparison of the CHS response in mice with normal and disinfected skin, or skin colonized with HutU+/- strains, provided functional evidence that the presence of HutU+ bacteria limits the immunosuppressive effect of cis-UCA. Furthermore, topical application of the urocanase inhibitor, dipeptide glycylglycine, restricted the metabolism of cis-UCA by HutU+bacteria and restored immunosuppression. Overall, our results provide mechanistic evidence that certain bacterial species of the skin microbiome can consume the UVB mediator cis-UCA, influence its concentration, and thereby regulate UV-induced immunosuppression.