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• W2366525140 abstract "Atopic dermatitis (AD) is a chronic pruritic, inflammatory skin disease caused by various factors. The pathogenesis of AD is a complex mechanism. Patients with AD are sensitive to Dermatophagoides farinae (DfE), and upon exposure, macrophages are known to accumulate in acutely or chronically inflamed skin 1. There are two major pathways of the macrophage activation, the classical M1 pathway and the alternative M2 pathway. Activated M1 macrophage secretes large amounts of proinflammatory mediators, which are associated with tissue damage. On the other side, the M2 phenotype is thought to improve tissue repair after inflammation or injury 2. Flavonoid naringenin is found in most citrus fruits, grapefruit and tomato skin. The pharmacological effects of naringenin are well known, such as antioxidant and anti-inflammatory activities. Recent in vitro studies reveal that the polyphenol naringenin effectively suppressed proinflammatory factors, cytokine and chemokine expressions in inflammation 3. In this study, we sought to investigate the effects of naringenin on skin inflammation, proinflammatory cytokines and M1 to M2 macrophage polarization shifts in AD NC/Nga mouse model. For a detailed explanation of the experimental design, see Supporting Information (Data Appendix S1) The dermatitis score of the naringenin treatment group decreased and became significantly different from that of the group AD mice (Fig. S1 and S2a). Haematoxylin and eosin (H&E) and toluidine blue staining of skin sections revealed hyperkeratosis, parakeratosis, acanthosis/spongiosis and infiltrated mast cells in the skin of AD mice, and these changes were attenuated by naringenin treatment (Fig. S2b-b1&c-c1). The protein expression of cluster of differentiation (CD)68, interferon (IFN)-γ, interleukin (IL)-6, tumor necrosis factor (TNF)-α, TNF receptor (TNFR)1 and IL-1β was significantly increased in AD mice, and these changes were significantly attenuated by naringenin treatment (Fig. 1a–a6). The protein expression of COX2, HMGB1, RAGE, p-ERK1/2, p-NFκB p65 and galectin-3 was significantly increased in AD mice, and these changes were significantly attenuated by naringenin treatment (Fig. 1b–b6). Immunohistochemical staining showed that the M2 marker CD36- and IL-10-positive cells were significantly downregulated in the skin section of AD mice, and these changes were restored by naringenin treatment (Fig. 2). In our work, the most crucial findings were as follows: (a) naringenin treatment sharply suppresses M1-like macrophage phenotype, HMGB1 cascade and inflammatory cytokine levels in AD mice. (b) Naringenin activates anti-inflammatory gene expression by switching M1 to M2 phenotype and leads to increased CD36 and IL-10. (c) As a result, naringenin alleviates AD symptoms, and infiltrated mast cells. Numerous previous studies strongly suggest that naringenin could regulate proinflammatory factors and inflammatory cytokine levels and their function, but the potential mechanism of naringenin in regulating M1 and M2 macrophage polarization in AD has not been studied. In the present study, we show for the first time that naringenin regulates macrophage polarization and skin inflammation in DfE-triggered AD in NC/Nga mice. Macrophages, the guard of innate immunity, take residence in nearly every tissue, and they play an imperative role in the resolution of tissue injury (M1 phenotype). The Th1 cytokine IFN-γ can promote macrophage polarization to a ‘classical’ or M1 phenotype. Interestingly, in this study, the AD mouse skin had increased expression of the M1 marker CD68, whereas treatment with naringenin effectively suppressed its expression. In addition, extensive experimental results showed that the activation of the macrophage M1 phenotype is generally associated with elevated levels of proinflammatory factors and cytokines, which play important roles in skin inflammation 4. Notably, in this present study, we found that naringenin treatment effectively suppressed M1-type markers. These data strongly suggest that the exposure to DfE modulates the macrophages into a state with increased capacity to produce proinflammatory factors and cytokines associated with M1-like phenotype, which were ameliorated by naringenin treatment. Moreover, numerous previous studies reported that the polarization of M1 macrophage skews the secretion of HMGB1 5. Very recently, we have reported that the translocated HMGB1 binds to RAGE and activates ERK1/2 and NFκB p65 signalling, which triggers inflammatory and proinflammatory cytokines 6, 7. Interestingly, in our study, naringenin modulated the HMGB1, RAGE, ERK1/2 and NFκB p65 expressions in the skin of AD mice. This finding confirms that M1-like macrophage might activate HMGB1 danger signalling to induce skin lesions in AD mice and treatment with naringenin can modulate these danger signalling pathway in AD mice. On the other hand, the alternative or M2 phenotype (anti-inflammatory) is induced by IL-10. The M2 macrophages express high levels of IL-10 and CD36 antigen 8. Injury in the skin rapidly induces the responses of M1 macrophages, and then, this response is shifted into M2 macrophage polarization 9. Therefore, switching macrophages from M1 into M2 phenotype can promote the skin repair. Interestingly, in our study, the M2 phenotypes such as IL-10 and CD36 levels were significantly restored by naringenin treatment. These findings demonstrated that the naringenin treatment might reverse M1-polarized macrophages to M2 phenotypes, suggesting that naringenin-mediated anti-inflammatory function can be effective irrespective of the phenotype of macrophages. Our findings suggest that naringenin may be an effective therapeutic agent that can be used to reduce the development of skin inflammation. This research was supported by Kakenhi grant, Japan (23602012 and 26460239). VK and KW contributed to study conception and design; VK and SA performed experiments and drafted the manuscript; VP, RS and RA performed immunohistochemical staining; MH, VVG and VK analysed and interpreted the data; RAT, SA, MN and KW revised the article, critically for important intellectual content; KS, KU and PK advised on inflammation signalling. The authors declare that there are no conflict of interests. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2366525140 date "2016-05-01" @default.
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• W2366525140 title "Naringenin ameliorates skin inflammation and accelerates phenotypic reprogramming from M1 to M2 macrophage polarization in atopic dermatitis <scp>NC</scp>/Nga mouse model" @default.
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• W2366525140 doi "https://doi.org/10.1111/exd.12962" @default.
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