Reply to Slominski et al.: UVB irradiation induces proenkephalin+ regulatory T cells with a wound-healing function
Reply to Slominski et al.: UVB irradiation induces proenkephalin+ regulatory T cells with a wound-healing function
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回复 Slominski 等人：UVB 照射诱导脑啡肽原调节性 T 细胞具有伤口愈合功能
DOI：
10.1073/pnas.2021919118
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Yamazaki Sayuri
中科院分区：
文献类型：
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作者：
Shime Hiroaki;Odanaka Mizuyu;Tsuiji Makoto;Matoba Takuma;Imai Masaki;Yasumizu Yoshiaki;Uraki Ryuta;Minohara Kiyoshi;Watanabe Maiko;Bonito Anthony John;Fukuyama Hidehiro;Ohkura Naganari;Sakaguchi Shimon;Morita Akimichi;Yamazaki Sayuri
Foxp 3 + CD 25 + CD 4+调节性T（Treg）细胞占外周CD 4 + T细胞的约10%，并抑制小鼠和人的多种免疫应答（1）。我们最近的报告（2）显示，通过紫外线B（UVB）暴露扩增的表达脑啡肽原（PENK）的Treg细胞促进伤口愈合。来自Slominski等人的信(3)指出皮肤驻留细胞产生脑啡肽和其他神经肽，并且在UVB照射后一天内早期检测到角质形成细胞、成纤维细胞和黑素细胞发挥的皮肤神经内分泌活性（3-6），尽管他们没有说明皮肤T细胞产生的PENK的可能作用（3-6）。在回应他们的评论时，我们想强调的是，我们研究的重点是研究皮肤Treg细胞的独特特征，这些细胞通过UVB照射扩增至约60%的CD 4 + T细胞，在照射后7天达到扩增峰值（7，8）。通过进一步推进这一发现，我们发现通过UVB照射扩增的皮肤Treg细胞表达PENK以及伤口愈合相关基因，包括编码双调蛋白（AREG）的Areg，这是Treg细胞分泌的一种关键组织修复因子（2）。此外，我们通过耗尽表达Foxp 3的Treg细胞证明了PENK+ Treg细胞对于UVB照射后促进伤口愈合是必需的，并且Treg细胞衍生的PENK或AREG在促进皮肤外植体中的角质形成细胞生长中起关键作用（2）。这些结果强烈表明，PENK+ Treg细胞有助于促进UVB照射后的伤口愈合（2）。Slominski等人(3)也表明昼夜变化对皮质类固醇水平的影响。与内源性激素（如涉及下丘脑-垂体-肾上腺轴的皮质类固醇）一样，免疫细胞也受到小鼠昼夜节律的影响（9）。考虑到这些可能性，我们采取预防措施，在一天的固定时间进行所有实验，包括血浆采集（2）。此外，随着小鼠在生理和应激条件下可以测量血浆皮质醇的报道（10），我们测量了创伤应激下的糖皮质激素水平：即在创伤后2天测量血浆皮质醇水平，即UVB照射后8天。这一时间与测量UVB照射应激影响的时间不同，UVB照射刺激糖皮质激素的产生不到一天（3，5，6）。即使糖皮质激素在一周后仍在局部或全身产生，值得注意的是，UVB照射在我们的实验环境中促进伤口愈合，与糖皮质激素对伤口愈合的抑制作用相反。我们以前报道过紫外线疗法扩增了银屑病患者的Treg细胞（11）。因此，紫外线扩增的Treg细胞也可能在人体中产生PENK，尽管需要在人体中进行进一步研究。总之，我们的报告清楚地表明，UVB照射诱导PENK+ Treg细胞表达具有伤口愈合功能的独特基因谱。
Foxp3+ CD25+ CD4+ regulatory T (Treg) cells constitute about 10% of peripheral CD4+ T cells and suppress a variety of immune responses in mice and humans (1). Our recent report (2) shows that proenkephalin (PENK)-expressing Treg cells expanded by ultraviolet B (UVB) exposure promoted wound healing. The Letter from Slominski et al.(3) points out that skin-resident cells produce enkephalins and other neuropeptides and that skin neuroendocrine activity exerted by keratinocytes, fibroblasts, and melanocytes was detected early after UVB irradiation within a day (3–6), although they did not address possible roles of PENK produced by skin T cells (3–6). In responding to their comments, we would like to emphasize that the focus of our study is to investigate unique features of skin Treg cells that were expanded by UVB irradiation to about 60% of CD4+ T cells, with a peak of their expansion 7 d after irradiation (7, 8). By further advancing this finding, we have found that skin Treg cells expanded by UVB irradiation expressed PENK and also wound-healing–related genes including Areg encoding amphiregulin (AREG), a key tissue repair factor secreted by Treg cells (2). Moreover, we demonstrated by depleting Foxp3-expressing Treg cells that PENK+ Treg cells were essential for promoting wound healing after UVB irradiation and that Treg cell-derived PENK or AREG played a key role in promoting keratinocyte outgrowth in skin explants (2). These results strongly indicate that PENK+ Treg cells contribute to promoting wound healing following UVB irradiation (2). Slominski et al.(3) also suggest influence of diurnal changes on corticosteroid levels. As well as endogenous hormones such as corticosteroids involving the hypothalamic–pituitary–adrenal axis, immune cells are affected by diurnal rhythmicity in mice (9). By considering these possibilities, we took precaution to perform all experiments including plasma collection at a fixed time of the day (2). In addition, with the report that plasma cortisol can be measured in mice under physiological and stressful conditions (10), we measured the glucocorticoid level under the stress due to wounding: that is, plasma cortisol levels were measured 2 d after wounding, which was 8 d after UVB irradiation. This timing was different from the one to measure the effects of the stress of UVB irradiation, which stimulated the production of glucocorticoids less than a day (3, 5, 6). Even if glucocorticoids were still being produced locally or systemically a week later, it is of note that UVB irradiation promoted wound healing in our experimental settings, contrary to the inhibitory effect of glucocorticoids on wound healing. We previously reported that UV-phototherapy expanded Treg cells in psoriatic patients (11). It is thus likely that UV-expanded Treg cells produce PENK in humans as well, although further study is required in humans. In conclusion, our report has clearly shown that UVB irradiation induces PENK+ Treg cells expressing unique gene profiles with a wound-healing function.