Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses.
Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses.
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DOI：
10.1016/j.jaci.2014.07.036
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Larregina AT
中科院分区：
文献类型：
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作者：
Sumpter TL;Ho CH;Pleet AR;Tkacheva OA;Shufesky WJ;Rojas-Canales DM;Morelli AE;Larregina AT
特应性疾病的有效发展需要过敏原和佐剂之间的相互作用，以启动和放大潜在的炎症反应。P物质（SP）和血激肽-1（HK-1）是通过神经激肽-1受体（NK 1 R）发出信号以促进炎症的神经肽。肥大细胞引发特应性疾病的症状和组织效应，在FcεRI通过Ag-IgE复合物交联后分泌TNF和IL-6（FcεRI-MCs）。此外，MC表达NK 1 R，表明NK 1 R激动剂对FcεRI-MC介导的病理具有佐剂作用，但缺乏针对MC生物学相关方面的深入研究。研究NK 1 R信号通路的作用以及SP和HK-1作为FcεRI-MC介导的过敏性疾病的潜在佐剂的各自作用。使用来自C57 BL/6-野生型（WT）或NK 1 R −/−小鼠的骨髓（BM）MCs研究Fcε RI激活MCs的NK 1 R信号传导的作用。从Tac 1 −/−小鼠或Tac 4 siRNA培养后产生的BMMC用于解决SP和HK-1的亲和力。使用WT或NK 1 R-/-BMMC重建的WT、NK 1 R-/-和c-KitW-sh/W-sh小鼠用于评估FcεRI-MC介导的被动局部和全身过敏反应和气道炎症上的NK 1 R信号传导。Fcε RI激活的MC上调NK 1 R和HK-1转录和蛋白质合成，而不改变SP。在正信号循环中，HK-1通过MC脱颗粒促进TNF和IL 6分泌，并通过PI 3 K/Akt/NFκB途径促进后者蛋白质合成。在体内，NK 1 R信号传导是被动局部和全身过敏反应和慢性气道炎症的发展所必需的。MC的Fcε RI刺激促进HK-1的自分泌分泌，HK-1通过NK 1 R发出信号，为FcεRI-MC介导的疾病的有效发展提供抑制。
Efficient development of atopic diseases requires interaction between allergen and adjuvant to initiate and amplify underlying inflammatory responses. Substance P (SP) and hemokinin-1 (HK-1) are neuropeptides that signal via the neurokinin-1 receptor (NK1R) to promote inflammation. Mast cells initiate the symptoms and tissue effects of atopic disorders, secreting TNF and IL-6 following FcεRI crosslinking by Ag-IgE complexes, (FcεRI-MCs). Additionally, MCs express the NK1R suggesting an adjuvant role of NK1R agonists for FcεRI-MC mediated pathologies, however in depth research addressing this relevant aspect of MC biology is lacking. To investigate the effect of NK1R-signaling and the individual roles of SP and HK-1 as potential adjuvants for FcεRI-MC mediated allergic disorders. Bone marrow (BM) MCs derived from C57BL/6-wild type (WT) or NK1R−/− mice were used to investigate the effects of NK1R signaling of FcεRI-activated MCs. BMMCs generated from Tac1−/− mice or following culture with Tac4 siRNA were used to address the adjuvancy of SP and HK-1. WT, NK1R−/− and c-KitW-sh/W-sh mice reconstituted with WT or NK1R−/− BMMCs were utilized to evaluate NK1R signaling on FcεRI-MC-mediated passive local and systemic anaphylaxis and airway inflammation. FcεRI-activated MCs up-regulated NK1R and HK-1 transcripts and protein synthesis, without modifying SP. In a positive signaling loop, HK-1 promoted TNF and IL6 secretion by MC degranulation and protein synthesis the later via the PI3K/Akt/NFκB pathways. In vivo, NK1R signaling was necessary for development of passive local and systemic anaphylaxis and chronic airway inflammation. FcεRI-stimulation of MCs promotes autocrine secretion of HK-1 which signals via NK1R to provide adjuvancy for efficient development of FcεRI-MC-mediated disorders.