Deng Qirui,Liu Xinyan,Wen Xiujuan,Huang Hao,Tang Hongfeng
The aim of this study was to investigate how ultraviolet B (UVB) light regulates AP-1 expression via the β2-adrenergic receptor (β2-AR) in epidermal keratinocytes, which in turn regulates melanin synthesis in melanocytes, thereby modulating downstream melanin production in skin hair follicles and altering mouse skin color. We established a UV-irradiated mouse model to investigate the effects of UV radiation on changes in skin color. By measuring changes in the expression of genes related to cutaneous sympathetic nerves, norepinephrine synthesis and melanin synthesis, we investigated the relationship between β2-AR expression and cutaneous melanogenesis and determined the localization of β2-AR in cells. The results of the siRNA-mediated transfection of keratinized cells with downregulated β2-AR expression were further verified in vitro. Our results suggest that UVB alters the color of the dorsal skin in mice by activating the AP-1/IL-6 pathway, which triggers the sympathetic release of norepinephrine, thereby increasing β2-AR expression in keratinocytes. Overall, our study improves the current understanding of how UVB light influences skin color changes and highlights the complex interplay between ultraviolet radiation and skin physiology.
Wei-Jia Yu,Wen-Xi Jiang,Shu-Jing Liu,Hui-Hua Li,Qiu-Yue Lin
Rationale: Infiltration of immune cells into the heart plays a crucial role in the transition from adaptive hypertrophy to heart failure (HF) following chronic pressure overload. However, the key factors in myeloid cells that regulate this process are still not well defined. Here, we studied the functional role of S100A8/A9 in myeloid cells during this transition. Methods: Cardiac hypertrophy and HF models were induced by transverse aortic constriction (TAC) for 1 to 4 weeks. The heterogeneity of CD45 + immune cells and the cellular sources of S100A8/A9 were analyzed using published single-cell RNA sequencing datasets. The effects of S100A8/A9 on TAC-induced hypertrophy and HF were verified in S100A9 knockout (KO) and bone marrow (BM)-chimeric mice and in an in vitro coculture system. Results: S100A8/A9 levels were significantly increased in HF patients and in TAC-induced HF model mice. Moreover, the TAC-induced transition from adaptive hypertrophy to HF was significantly attenuated in S100A9-KO mice and WT mice transplanted with S100A9-KO BM cells. Mechanistically, TAC-stimulated upregulation of S100A8/A9 in neutrophils induced an early inflammatory response and adaptive hypertrophy through activation of the p38 MAPK/JNK/AP-1 pathway, leading to increased production of IL-1β and chemokines (CCL2 and CCL6). These chemokines promoted the infiltration of CCR2 + macrophages to the damaged heart. Therefore, they exhibited upregulation of S100A8/A9, which led to exacerbation of inflammation, cardiac hypertrophy and fibrosis via activation of the NF-κB/NLRP3, AKT/Calcineurin A and TGF-β/Smad2 signaling pathways. Additionally, treating WT mice with the S100A9 inhibitor ABR-238901 prevented TAC-induced cardiac hypertrophy-related dysfunction. Conclusion: The present findings establish an S100A8/A9-related axis between myeloid cells and cardiac cells that drives the pressure overload-induced transition from hypertrophy to HF, suggesting that S100A8/A9 is a promising therapeutic target for this disease.
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