Immunity:伤口愈合瘙痒治疗有望,IL-31才是元凶!

2020-07-21 生物探索 生物探索

细胞因子TGF-β能够诱导真皮树突状细胞表达IL-31,从而激活感觉神经元并产生瘙痒。

皮肤伤口愈合往往伴随局部的瘙痒感。烧伤等范围更大的伤口不仅愈合更加困难,这种痒反应也更加强烈。相信大部分人都体会过伤口愈合后期的瘙痒感,这种不适究竟是如何产生的呢?能不能通过医学手段控制呢?

《Immunity》杂志2020年7月15日在线发表了美国国家卫生研究院陈万军团队的一项最新研究成果。作者发现,细胞因子TGF-β能够诱导真皮树突状细胞表达IL-31,从而激活感觉神经元并产生瘙痒。

皮肤伤口愈合是一个高度协调的、存在有序及动态炎症反应的过程,涉及到多种生长因子和细胞因子。然而,在伤口愈合过程中,导致瘙痒感产生的主要因素和免疫调节瘙痒的基本机制仍然难以捉摸。

研究人员对部分手术后患者进行调查,并对伤口愈合模型小鼠进行视频研究,确定了伤口愈合痒反应的高峰在皮肤外伤后5天。其后,使用RNA-seq、QPCR及ELISA法对模型小鼠伤口皮肤检测,均提示IL-31的表达在瘙痒反应高峰期升高。为了明确IL-31在痒反应中的作用,研究人员构建了IL-31敲除鼠。与野生型小鼠相比,其抓挠伤没有明显增加,也就是说,IL-31敲除鼠伤口瘙痒较轻。

图片来源:immunity

研究人员进一步探讨了IL-31引发痒反应的机制。他们发现,Il31ra、Trpv1(辣椒素受体)和Nppb的表达在感觉神经元的愈合过程中被调节,而Trpa1的表达没有显着变化。而在体外条件下,IL-31治疗24小时可以增强DRG神经元中辣椒素(50 nM)刺激的钙内流。此外,IL-31还可以诱导Stat3的磷酸化。研究人员对mut-Stat3伤口愈合模型小鼠进行IL-31注射发现,其抓挠伤没有明显增加,这些结果表明,IL-31可以增加感觉神经元中关键信号转导分子的表达,使神经敏感性增加。

图片来源:immunity

接下来,研究人员揭示了伤口愈合中IL-31的来源。通过对伤口皮肤中的免疫细胞进行分选并检测IL-31表达,研究人员发现T细胞或B细胞并非伤口皮肤中IL-31的主要来源,而树突状细胞(DC)的IL-31表达最高。进一步验证发现,与正常皮肤相比,伤口皮肤的CD11c细胞数量更高。并且,与野生型小鼠相比,cDC耗竭小鼠的抓挠伤没有明显增加。

图片来源:immunity

那么,究竟哪些因素促使了伤口皮肤IL-31表达的增加呢?据报道,细胞因子IL-1β,IL-6,IL-17a,转化生长因子β1(TGF-β1)和肿瘤坏死因子α(TNF-α)为协调伤口修复的重要参与者。因此,研究人员测试了这些细胞因子在体外皮肤cDC2中诱导IL-31表达的影响。出乎意料的是,只有TGF-β1大幅提高了正常皮肤中Il31表达。

此外,在TGF-β受体1(Tgfbr1)敲除小鼠和Smad3?/?小鼠中,IL-31的产生和小鼠抓挠伤均明显减少,提示TGF-β在皮肤 cDC2中诱导IL-31升高。

图片来源:immunity

此研究中,研究人员发现,在皮肤伤口愈合的过程中,cDC2s通过TGF-β-IL-31轴增强了感觉神经元敏感性,导致伤口瘙痒的发生。

图片来源:immunity

IL-31可能是通过上调涉及信号接收(Il31Ra),信号转导(Trpv1)和信号传输(Nppb)分子表达来增加感觉神经元活动。这些分子表达与 Stat3 相关,表明Stat3可能是IL-31依赖性瘙痒的一个潜在治疗靶点。

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. DOI:https://doi.org/10.1016/j.immuni.2020.06.023.

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  5. [GetPortalCommentsPageByObjectIdResponse(id=2030404, encodeId=6d8020304046a, content=<a href='/topic/show?id=25079e7287' target=_blank style='color:#2F92EE;'>#Immunity#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=9772, encryptionId=25079e7287, topicName=Immunity)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/C4Qhy5XHSe503Qbjzc1UtDR83BCv66o6P2XRedX9ohsNGa3uEVicFFk2qkuX5zBSmpicepFySBrwoYknhqMdKmtw/132, createdBy=1aca2500179, createdName=12498d2fm51(暂无昵称), createdTime=Sun Apr 25 20:01:32 CST 2021, time=2021-04-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1302583, encodeId=079b130258397, content=<a href='/topic/show?id=b541e1219dc' target=_blank style='color:#2F92EE;'>#瘙痒#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71219, encryptionId=b541e1219dc, topicName=瘙痒)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=9d17305, createdName=listen318, createdTime=Thu Jul 23 11:01:32 CST 2020, time=2020-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1309905, encodeId=45d113099051f, content=<a href='/topic/show?id=5e6926003ae' target=_blank style='color:#2F92EE;'>#伤口愈合#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=26003, encryptionId=5e6926003ae, topicName=伤口愈合)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8949377, createdName=chenzhuanggui, createdTime=Thu Jul 23 11:01:32 CST 2020, time=2020-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=803737, encodeId=1f7a803e372a, content=赞, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTIqlnCibWjuDUAgaCHwFuMzAuMjyriarZStfbH4awkBQFoYtqff6tfJDz5D2lgbIicHCJXZxibs2Jr52Q/132, createdBy=c3db5138446, createdName=1466f1b5m86(暂无昵称), createdTime=Tue Jul 21 20:48:08 CST 2020, time=2020-07-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=803731, encodeId=2751803e31b7, content=<a href='/topic/show?id=82a83202521' target=_blank style='color:#2F92EE;'>#创伤修复#</a>古人有一个说法,创口愈合的前面会痒,说明痒,有助于创口愈合,但是过头了愈合以后会持续发痒, beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=32025, encryptionId=82a83202521, topicName=创伤修复)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220519/c2ab253484ee4527a2d4e9589a4821ac/45de9bf494a54becb2ea4369c9d11e85.jpg, createdBy=7a3710, createdName=lovetcm, createdTime=Tue Jul 21 20:31:09 CST 2020, time=2020-07-21, status=1, ipAttribution=)]
    2020-07-21 lovetcm

    #创伤修复#古人有一个说法,创口愈合的前面会痒,说明痒,有助于创口愈合,但是过头了愈合以后会持续发痒

    0

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