Sumpter Tina L, Ho Chin H, Pleet Anna R, Tkacheva Olga A, Shufesky William J, Rojas-Canales Darling M, Morelli Adrian E, Larregina Adriana T
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
J Allergy Clin Immunol. 2015 Apr;135(4):1019-1030.e8. doi: 10.1016/j.jaci.2014.07.036. Epub 2014 Sep 4.
Efficient development of atopic diseases requires interactions between allergen and adjuvant to initiate and amplify the underlying inflammatory responses. Substance P (SP) and hemokinin-1 (HK-1) are neuropeptides that signal through the neurokinin-1 receptor (NK1R) to promote inflammation. Mast cells initiate the symptoms and tissue effects of atopic disorders, secreting TNF and IL-6 after FcεRI cross-linking by antigen-IgE complexes (FcεRI-activated mast cells [FcεRI-MCs]). Additionally, MCs express the NK1R, suggesting an adjuvant role for NK1R agonists in FcεRI-MC-mediated pathologies; however, in-depth research addressing this relevant aspect of MC biology is lacking.
We sought 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-derived mast cells (BMMCs) from C57BL/6 wild-type (WT) or NK1R(-/-) mice were used to investigate the effects of NK1R signaling on FcεRI-MCs. BMMCs generated from Tac1(-/-) mice or after culture with Tac4 small interfering RNA were used to address the adjuvancy of SP and HK-1. WT, NK1R(-/-), and c-Kit(W-sh/W-sh) mice reconstituted with WT or NK1R(-/-) BMMCs were used to evaluate NK1R signaling on FcεRI-MC-mediated passive local and systemic anaphylaxis and on airway inflammation.
FcεRI-activated MCs upregulated NK1R and HK-1 transcripts and protein synthesis, without modifying SP expression. In a positive signaling loop HK-1 promoted TNF and IL-6 secretion by MC degranulation and protein synthesis, the latter through the phosphoinositide 3-kinase/Akt/nuclear factor κB pathways. In vivo NK1R signaling was necessary for the development of passive local and systemic anaphylaxis and airway inflammation.
FcεRI stimulation of MCs promotes autocrine secretion of HK-1, which signals through NK1R to provide adjuvancy for efficient development of FcεRI-MC-mediated disorders.
特应性疾病的有效发展需要变应原与佐剂之间的相互作用来启动和放大潜在的炎症反应。P物质（SP）和血红蛋白-1（HK-1）是通过神经激肽-1受体（NK1R）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，在抗原-IgE复合物交联FcεRI后分泌肿瘤坏死因子（TNF）和白细胞介素-6（FcεRI激活的肥大细胞[FcεRI-MCs]）。此外，肥大细胞表达NK1R，提示NK1R激动剂在FcεRI-MC介导的病理过程中起佐剂作用；然而，缺乏针对肥大细胞生物学这一相关方面的深入研究。
我们试图研究NK1R信号传导的作用以及SP和HK-1作为FcεRI-MC介导的过敏性疾病潜在佐剂的各自作用。
使用来自C57BL/6野生型（WT）或NK1R（-/-）小鼠的骨髓来源的肥大细胞（BMMCs）来研究NK1R信号传导对FcεRI-MCs的影响。使用来自Tac1（-/-）小鼠或用Tac4小干扰RNA培养后产生的BMMCs来探讨SP和HK-1的佐剂作用。用WT或NK1R（-/-）BMMCs重建的WT、NK1R（-/-）和c-Kit（W-sh/W-sh）小鼠用于评估NK1R信号传导对FcεRI-MC介导的被动局部和全身过敏反应以及气道炎症的影响。
FcεRI激活的肥大细胞上调NK1R和HK-1转录本及蛋白质合成，而不改变SP表达。在一个正反馈信号环路中，HK-1通过肥大细胞脱颗粒和蛋白质合成促进TNF和IL-6分泌，后者通过磷脂酰肌醇3-激酶/蛋白激酶B/核因子κB途径。在体内，NK1R信号传导对于被动局部和全身过敏反应以及气道炎症的发展是必需的。
FcεRI对肥大细胞的刺激促进HK-1的自分泌，HK-1通过NK1R发出信号，为FcεRI-MC介导的疾病的有效发展提供佐剂作用。
