Abstract
Carbon dioxide (CO2) is the predominant gas molecule emitted during aerobic respiration. Although CO2 can improve blood circulation in the skin via its vasodilatory effects, its effects on skin inflammation remain unclear. The present study aimed to examine the anti-inflammatory effects of CO2 in human keratinocytes and skin. Keratinocytes were cultured under 15% CO2, irradiated with ultraviolet B (UVB), and their inflammatory cytokine production was analyzed. Using multiphoton laser microscopy, the effect of CO2 on pH was observed by loading a three-dimensional (3D)-cultured epidermis with a high-CO2 concentration formulation. Finally, the effect of CO2 on UVB-induced erythema was confirmed. CO2 suppressed the UVB-induced production of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) in keratinocytes and the 3D epidermis. Correcting medium acidification with NaOH inhibited the CO2-induced suppression of TNFα and IL-6 expression in keratinocytes. Moreover, the knockdown of H+-sensing G protein-coupled receptor 65 inhibited the CO2-induced suppression of inflammatory cytokine expression and NF-κB activation and reduced CO2-induced cyclic adenosine monophosphate production. Furthermore, the high-CO2 concentration formulation suppressed UVB-induced erythema in human skin. Hence, CO2 suppresses skin inflammation and can be employed as a potential therapeutic agent in restoring skin immune homeostasis.
Highlights
The skin is the largest organ of the human body
Human epidermal keratinocytes isolated from neonatal foreskin (HEKn) cultured in 15% CO2 displayed a significantly lower ultraviolet B (UVB)-induced increase in tumor necrosis factor-α (TNFα) and IL-6 mRNA expression (Fig. 1a,b) alongside significantly lower TNFα and IL-6 protein levels in the culture supernatant (Fig. 1c,d)
The 3D epidermis treated with the high-CO2 concentration formulation (CO2) displayed a significantly lower UVB-induced increase in TNFα and IL-6 mRNA expression than the 3D epidermis treated with the control (Ctl) formulation (Fig. 1e,f)
Summary
The skin is the largest organ of the human body. It acts as a protective covering while serving as a barrier separating the body from the external environment. Hydrogen sulfide and nitric monoxide are well-known and are involved in physiological functions in the skin, such as vasodilation, cell proliferation, apoptosis, and inflammation[15,16] These facts suggest that gasotransmitters play an important role in maintaining skin homeostasis. CO2 has been shown to suppress lipopolysaccharide (LPS)-induced inflammatory responses in several blood cell types and lung-derived cell lines[20,21,22]. This points to CO2 as a by-product of aerobic respiration and to its role as a gasotransmitter in suppressing inflammatory responses. The effect of C O2 on UV-induced erythema was evaluated in human skin
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