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Immunity:陈万军团队揭示TGF-β促进树突状细胞分泌白介素-31是伤口愈合过程中产生瘙痒的主要原因

2020-07-28 BioArt

神经系统可通过细胞间接触以及可溶性因子的释放调节免疫反应。尽管已知能引起瘙痒的因素有很多,但伤口愈合过程中免疫反应介导的瘙痒的主要因素和潜在机制仍然并不清楚。

神经系统与免疫系统之间的相互作用对于机体稳态的维持以及疾病的发生发展十分重要,越来越多的研究表明神经系统可通过细胞间接触以及可溶性因子的释放调节免疫反应。但是,鲜有报道阐述免疫系统对神经系统尤其是感觉神经的调节。皮肤伤口愈合是一个高度有序的过程,涉及局部炎症及多种生长因子和细胞因子的释放;同时,在愈合过程的后期常可出现瘙痒症状。瘙痒一般是由其相关的感觉神经元兴奋引起。当引起瘙痒的小分子与感觉神经元上的受体结合时,神经元上的痒觉相关离子通道如TRPV1会被打开,引起阳离子尤其是钙离子内流,造成该神经元兴奋,从而使其在背根神经节及三叉神经节等换元处分泌一种瘙痒特异的神经递质NPPB,将瘙痒信号换元后传至大脑。然而,尽管已知能引起瘙痒的因素有很多,但伤口愈合过程中免疫反应介导的瘙痒的主要因素和潜在机制仍然并不清楚。

美国国立卫生研究院牙及颅颌面研究所陈万军 (NIH, NIDCR, Wanjun Chen) 实验室在Immunity在线发表题为 The cytokine TGF-β induces interleukin-31 expression from dermal dendritic cells to activate sensory neurons and stimulate wound itching 的最新论文。该研究表明,伤口愈合过程中局部的免疫调节细胞因子TGF-β增高可促进真皮层内的2型树突状细胞(cDC2)分泌白介素-31(IL-31),使得具有IL-31受体的瘙痒相关神经元敏感并兴奋,从而造成伤口愈合过程中产生局部瘙痒。

该研究通过录像观察小鼠皮肤伤口愈合模型,发现小鼠伤口愈合第5天搔抓行为最频繁。通过对伤口愈合过程中的皮肤组织进行RNA测序,发现在所有已知与瘙痒相关的基因中,Il31在愈合第五天特异性的增高。而对Il31基因敲除小鼠的行为观察发现,该基因敲除鼠在皮肤愈合过程的搔抓行为大幅减少,证明了IL-31是引起伤口愈合过程中产生瘙痒的主要原因。

IL-31如何引起瘙痒?研究团队发现,小鼠伤口区域的背根神经节中高表达瘙痒相关的基因Il31ra,Trpv1及Nppb。用IL-31处理体外培养的感觉神经元,亦可使其高表达这些基因。同时,钙离子成像试验显示IL-31可使感觉神经元更为敏感。蛋白分析显示IL-31是通过Stat3信号通路发挥作用的,Stat3抑制剂可抑制IL-31对上述瘙痒基因的上调作用,而应用Stat3基因敲除鼠可极大减少IL-31造成的感觉神经元敏感。

IL-31从何处分泌?研究团队通过对伤口愈合第5天的皮肤组织进行的精准流式细胞分选,发现真皮层的cDC2表达Il31最高。将小鼠中的树突状细胞、朗格汉斯细胞、巨噬细胞分别剔除后进行行为学观察,只有剔除了树突状细胞的小鼠在伤口愈合时搔抓行为减少,最终判定真皮层的树突状细胞是产生IL-31的主要来源。

IL-31因何产生?研究团队通过流式细胞术分选出小鼠真皮层中cDC2并应用皮肤愈合中已知重要的各细胞因子分别对其进行处理,发现TGF-β可上调Il31在cDC2中的表达。将TGF-β处理后的cDC2注射回小鼠皮内,可使其出现抓搔行为。同时,研究团队发现TGF-b 受体在树突样细胞条件敲除小鼠(Cd11cCre Tgfr1f/f)其皮肤愈合过程中的抓搔行为减少,最终证明TGF-β促进cDC2分泌IL-31是伤口愈合过程中产生瘙痒的主要原因。

该论文的第一作者徐骏疾是陈万军教授团队的博士后,陈万军教授为通讯作者。参与该项研究的还有首都医科大学王松灵院士团队以及美国国立卫生研究院Mark Hoon教授团队。

原始出处:

Junji Xu, Peter Zanvit, Lei Hu, et al.The Cytokine TGF-β Induces Interleukin-31 Expression from Dermal Dendritic Cells to Activate Sensory Neurons and Stimulate Wound Itching.Immunity. 2020 Jul 8;S1074-7613(20)30278-8. doi: 10.1016/j.immuni.2020.06.023.

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    2020-09-28 changhe713
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    2020-09-26 docwu2019
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    2020-07-30 listen318
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胰腺癌可以说是当之无愧的癌王,转移快,复发率高,生存期短,就连免疫治疗这个大杀器都对它无可奈何。

Nature Methods:科学家们研发出一种人工受体,或将强化抗肿瘤疫苗

树突状细胞(DC)是一种功能强大的抗原呈递细胞,是抗肿瘤免疫疗法的关键细胞。现在,科学家们研发出一种人工受体,能够改善DC呈递抗原的方式,提高免疫细胞识别、攻击肿瘤细胞的效率。这一研究于1月22日在线发表在《Nature methods》期刊。

Cell Research:一招两用——树突状细胞关键调节因子LKB1功能终明了

日前,美国St. Jude儿童医院的研究人员发现了DC中在代谢与免疫过程中发挥重要调节作用的关键因子——LKB1,证实了其在维持正常的免疫稳态和保护性抗肿瘤免疫中的作用,并指出了其作为癌症和自身免疫疾病治疗的重要靶点的巨大潜能。

JCI:癌症疫苗更上一层楼!以单核代替树突,反其道而行获意外惊喜

数据显示,过去十年里,全球癌症发病率增长了22%以上,这个数字未来还将不断更新,癌症已经成为21世纪威胁人类健康的重要杀手之一。随着相关研究的深入,以树突状细胞(DC)为主的癌症疫苗成为了癌症攻克的新希望,但该疗法逐渐显露的问题,尤其是DC相关技术的困境严重影响了癌症疫苗的疗效与推广。

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