Abstract
Although sulfur-rich thermal waters have ancestrally been used in the context of dermatological conditions, a global mapping of the molecular effects exerted by H2S on human keratinocytes is still lacking. To fill this knowledge gap, we subjected cultured human keratinocytes to distinct amounts of the non-gaseous hydrogen sulfur donor NaHS. We first checked that H2S accumulated in the cytoplasm of keratinocytes under our experimental conditions andused a combination of proteomics, genomics and biochemical approaches to unravel functionally relevant H2S targets in human keratinocytes. We found that the identified targets fall into two main categories: (i) the oxidative stress response molecules superoxide dismutase 2 (SOD2), NAD(P)H quinone dehydrogenase 1 (NQO1) and culin 3 (CUL3) and (ii) the chemokines interleukin-8 (IL-8) and CXCL2. Interestingly, NaHS also stimulated the caspase-1 inflammasome pathway, leading to increased secretion of the pro-inflammatory molecule interleukin-18 (IL-18). Interestingly, the secretion of interleukin-1 beta (IL-1β) was only modestly impacted by NaHS exposure despite a significant accumulation of IL-1β pro-form. Finally, we observed that NaHS significantly hampered the growth of human keratinocyte progenitors and stem cells cultured under clonogenic conditions or as epidermal cell sheets. We conclude that H2S exerts specific molecular effects on normal human keratinocytes.
Highlights
Sulfur-rich thermal waters are an ancestral dermatological therapy which nowadays is used as an adjunct treatment for psoriasis and atopic dermatitis [1,2,3,4] and chronic skin wounds [4,5]
We found that the identified targets fall into two main categories: (i) the oxidative stress response molecules superoxide dismutase 2 (SOD2), NAD(P)H quinone dehydrogenase 1 (NQO1) and culin 3 (CUL3) and (ii) the chemokines interleukin-8 (IL-8) and CXCL2
We found that NaHS added to the culture media at a concentration of 0.25 mM induced a quick rise in H2S, irrespective of the presence or absence of cultured keratinocytes (Figure 1a)
Summary
Sulfur-rich thermal waters are an ancestral dermatological therapy which nowadays is used as an adjunct treatment for psoriasis and atopic dermatitis [1,2,3,4] and chronic skin wounds [4,5]. In order to mimic the impact of sulfur-rich spa waters on skin cells, previous works assessed the effects of NaHS on the proliferation, differentiation, adhesion properties and cytokine profile of cultured human keratinocytes [6,7,8,9,10] Under these experimental conditions, NaHS was notably reported to inhibit the synthesis of anti-inflammatory molecules such as IL-8 and IL-1β, which provided support for the use of sulfur-rich thermal waters for the treatment of psoriasis [7,9]. Our results show that NaHS inhibits the proliferation of human keratinocyte progenitors and stem cells, stimulates their secretion of specific pro-inflammatory cytokines and promotes the synthesis of molecules involved in antioxidative response These findings provide insights into the molecular effects exerted by sulfur-rich spa waters on skin cells and point to the potential role of H2S as a gaseous regulator of epidermal cell homeostasis
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