Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine.
Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine.
复制标题
DOI：
10.1053/j.gastro.2021.03.049
复制
发表时间：
2021-07
期刊：
影响因子：
29.4
通讯作者：
中科院分区：
文献类型：
--
作者：
对胆汁淤积性肝病瘙痒机制的有限理解阻碍了抗瘙痒治疗的发展。先前的研究表明溶血磷脂酸（LPA）是胆汁淤积性瘙痒症的潜在介质。在未处理小鼠、胆汁淤积小鼠和非人灵长类动物中检查了溶血磷脂酰胆碱（LPC）（LPA的前体）的瘙痒性。使用遗传和药理学方法、培养的角质形成细胞、离子通道生理学和结构计算建模研究了涉及角质形成细胞TRPV 4的LPC的促增殖性。通过体外和离体Ca 2+成像测定鉴定了由角质形成细胞分泌的microRNA-146 a（miR-146 a）对神经受体感觉神经元的激活。来自原发性胆汁性胆管炎患者的血清用于测量LPC和miR-146 a的水平。LPC在小鼠中具有强烈的毒性。皮肤角质形成细胞中的TRPV 4是LPC诱导的瘙痒和胆汁淤积小鼠瘙痒所必需的。三维结构建模、定点突变和通道功能分析表明，TRPV 4 C-末端基序用于LPC结合和通道激活。在角质形成细胞中，LPC激活TRPV 4诱导细胞外释放miR-146 a，其激活TRPV 1+感觉神经元以引起瘙痒。LPC和miR-146 a水平在伴有瘙痒的原发性胆管炎患者血清中均升高，并与瘙痒强度相关。此外，LPC和miR-146 a在胆汁淤积小鼠的血清中也增加，并在非人灵长类动物中引起瘙痒。我们将LPC鉴定为一种新型的胆汁淤积性促炎原，其通过上皮-感觉神经元串扰诱导瘙痒，从而直接激活皮肤角质形成细胞TRPV 4，其快速释放miR-146 a以激活皮肤神经支配的TRPV 1+促炎受体感觉神经元。我们的研究结果支持皮肤作为感觉器官的新概念，在胆汁淤积性瘙痒中发挥关键作用，超越肝脏，外周感觉神经元和中枢神经通路支持免疫感受。
Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of antipruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus. Pruritogenicity of lysophosphatidylcholine (LPC), LPA’s precursor, was examined in naïve mice, cholestatic mice, and nonhuman primates. LPC’s pruritogenicity involving keratinocyte TRPV4 was studied using genetic and pharmacologic approaches, cultured keratinocytes, ion channel physiology, and structural computational modeling. Activation of pruriceptor sensory neurons by microRNA-146a (miR-146a), secreted from keratinocytes, was identified by in vitro and ex vivo Ca2+ imaging assays. Sera from patients with primary biliary cholangitis were used for measuring the levels of LPC and miR-146a. LPC was robustly pruritic in mice. TRPV4 in skin keratinocytes was essential for LPC-induced itch and itch in mice with cholestasis. Three-dimensional structural modeling, site-directed mutagenesis, and channel function analysis suggested a TRPV4 C-terminal motif for LPC binding and channel activation. In keratinocytes, TRPV4 activation by LPC induced extracellular release of miR-146a, which activated TRPV1+ sensory neurons to cause itch. LPC and miR-146a levels were both elevated in sera of patients with primary biliary cholangitis with itch and correlated with itch intensity. Moreover, LPC and miR-146a were also increased in sera of cholestatic mice and elicited itch in nonhuman primates. We identified LPC as a novel cholestatic pruritogen that induces itch through epithelia-sensory neuron cross talk, whereby it directly activates skin keratinocyte TRPV4, which rapidly releases miR-146a to activate skin-innervating TRPV1+ pruriceptor sensory neurons. Our findings support the new concept of the skin, as a sensory organ, playing a critical role in cholestatic itch, beyond liver, peripheral sensory neurons, and central neural pathways supporting pruriception.
登录
查看更多内容
影响因子：
16.2
作者：
Han Q;Liu D;Convertino M;Wang Z;Jiang C;Kim YH;Luo X;Zhang X;Nackley A;Dokholyan NV;Ji RR
通讯作者：
Ji RR
TRPV4和TRPA1的小分子双抑制剂，用于炎症和疼痛的衰减。
影响因子：
4.6
作者：
Kanju P;Chen Y;Lee W;Yeo M;Lee SH;Romac J;Shahid R;Fan P;Gooden DM;Simon SA;Spasojevic I;Mook RA;Liddle RA;Guilak F;Liedtke WB
通讯作者：
Liedtke WB
影响因子：
4.6
作者：
Lee, Heeseung;Ko, Mei-Chuan
通讯作者：
Ko, Mei-Chuan
影响因子：
--
作者：
Dull, Miriam M;Kremer, Andreas E
通讯作者：
Kremer, Andreas E
DOI：
10.1002/hep.28265
发表时间：
2016-04
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Abu-Hayyeh S;Ovadia C;Lieu T;Jensen DD;Chambers J;Dixon PH;Lövgren-Sandblom A;Bolier R;Tolenaars D;Kremer AE;Syngelaki A;Noori M;Williams D;Marin JJ;Monte MJ;Nicolaides KH;Beuers U;Oude-Elferink R;Seed PT;Chappell L;Marschall HU;Bunnett NW;Williamson C
通讯作者：
Williamson C