Carbon dioxide inhibits UVB-induced inflammatory response by activating the proton-sensing receptor, GPR65, in human keratinocytes

Carbon dioxide (CO(2)) is the predominant gas molecule emitted during aerobic respiration. Although CO(2) 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 CO(2) in human keratinocytes and skin. Keratinocytes were cultured under 15% CO(2), irradiated with ultraviolet B (UVB), and their inflammatory cytokine production was analyzed. Using multiphoton laser microscopy, the effect of CO(2) on pH was observed by loading a three-dimensional (3D)-cultured epidermis with a high-CO(2) concentration formulation. Finally, the effect of CO(2) on UVB-induced erythema was confirmed. CO(2) 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 CO(2)-induced suppression of TNFα and IL-6 expression in keratinocytes. Moreover, the knockdown of H(+)-sensing G protein-coupled receptor 65 inhibited the CO(2)-induced suppression of inflammatory cytokine expression and NF-κB activation and reduced CO(2)-induced cyclic adenosine monophosphate production. Furthermore, the high-CO(2) concentration formulation suppressed UVB-induced erythema in human skin. Hence, CO(2) suppresses skin inflammation and can be employed as a potential therapeutic agent in restoring skin immune homeostasis.