Carbon dioxide inhibits UVB-induced inflammatory response by activating the proton-sensing receptor, GPR65, in human keratinocytes
Keimon Sayama, Katsuyuki Yuki, Keiichi Sugata, Satoko Fukagawa, Tetsuji Yamamoto, Shigaku Ikeda, Takatoshi Murase
Abstract
Abstract 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.