Skin Microbiome Modulates the Effect of Ultraviolet Radiation on Cellular Response and Immune Function

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The skin is colonized by a diverse microbiome intricately involved in various molecular and cellular processes within the skin and beyond. UV radiation is known to induce profound changes in the skin and modulate the immune response. However, the role of the microbiome in UV-induced immune suppression has been overlooked. By employing the standard model of contact hypersensitivity (using germ-free mice) we found diminished UV-induced systemic immune suppression in the presence of microbiome. Upon UV exposure, we found enhanced epidermal hyperplasia and neutrophilic infiltration in the presence and enhanced numbers of mast cells and monocyte or macrophages in the absence of microbiome.

Transcriptome analysis revealed a predominant expression of cytokine genes related to pro-inflammatory milieu in the presence versus immunosuppressive milieu (with increased interleukin-10) in the absence of microbiome. Collectively, microbiome abrogates the immunosuppressive response to UV by modulating gene expression and cellular microenvironment of the skin. Introduction The human skin is colonized by a diverse collection of microbes including bacteria, fungi, archaea, mites, and viruses. The majority of these microbes are commensals or transients that live in a mutualistic relationship with the skin's immune system, and recent studies indicate that the skin microbes influence gene expression in the skin (Meisel et al., 2018) and are involved in educating and modulating its immune response (Belkaid and Segre, 2014). Dysbiosis in the skin microbiome is linked to many skin pathologies such as acne, atopic dermatitis, and psoriasis (Zeeuwen et al., 2013). Ultraviolet radiation (UV-R), on the other hand, has long been known to affect immune response, playing a role in skin carcinogenesis and in certain inflammatory skin diseases including photodermatoses and photoaggravated conditions (Wolf et al., 2016b). UV-R is known to induce innate immunity and suppress adaptive immune responses in healthy individuals (Schwarz, 2010). UV-R-induced immune suppression is mediated through T cells (Schwarz, 2010), and the immunomodulating properties of UV-R are most often investigated by using the contact hypersensitivity (CHS) model in mice and in humans (Fourtanier et al., 2005, Kelly et al., 2000).

Furthermore, UV exposure is known to induce changes within the transcriptome of the skin and affect the gene expression of various biological processes that contribute to immune response (Sesto et al., 2002, Shen et al., 2016). Interestingly, a recent study reports the contribution of the skin microbiome to differential regulation of gene expression in the skin, most notably for the genes encoding Toll-like receptors (TLRs) and antimicrobial peptides (AMPs) and genes related to the interleukin (IL)-1 family (Meisel et al., 2018). The skin microbiome is also involved in regulating genes responsible for epidermal differentiation and development and in influencing wound healing (Canesso et al., 2014, Meisel et al., 2018). Although previous studies have shown the broad influence of UV-B on immune function, they have overlooked the potential contribution of the skin microbiome to this phenomenon (Patra et al., 2016, Patra et al., 2018). Therefore we employed the model of UV-induced suppression of induction of CHS in sterile, germ-free (GF) mice (totally devoid of microbiome) and found that the skin microbiome inhibited UV-induced immune suppression. Furthermore, in our transcriptome and histological analyses, we observed that a single UV dose induced several pro-inflammatory genes such as IL-1β, IL-6, and IL-18rap; increased microabscesses and neutrophilic infiltration in specific pathogen free (SPF) mouse skin versus induction of anti-inflammatory genes such as IL-10, IL-10ra, IL-20rb, and IL-7r; and increased numbers of mast cells, macrophages, and IL-10+ cells in GF skin. Collectively, our results show that the skin microbiome affords immune protection by orchestrating local cellular and innate immune responses to UV. Results Skin Microbiome Limits UV-Induced Suppression of Systemic Adaptive Immune Response UV-B is known to inhibit CHS responses to haptens such as dinitrofluorobenzene (DNFB). However, the role of skin microbiome in this induction of immune response has not yet been studied. We irradiated mice on the shaved dorsal skin (ears covered with black electrical tape) with a dose of 618 mJ/cm2 (equaling two minimal inflammatory doses; Figure S2).

Three days later, the mice were sensitized on the abdomen with 0.5% DNFB and challenged on the ears 5 days later with 0.2% DNFB (Figure 1A). The skin thickness was measured before and after challenge, and CHS response (as determined by skin swelling) was calculated for the different experimental groups. The presence of skin microbiome inhibited UV-induced suppression of induction of CHS in SPF mice exposed to UV-B before sensitization with DNFB. GF mice showed a significantly reduced CHS response compared with SPF mice (28.6% versus 59.5%) (Figure 1B). These results show that the absence of skin microbiome at the time of UV-B exposure enhanced immune suppression.