Spitsin Sergei, Pappa Vasiliki, Douglas Steven D
Department of Pediatrics, Division of Allergy and Immunology, Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Leukoc Biol. 2018 Jan 10. doi: 10.1002/JLB.3MIR0817-348R.
Substance P (SP) is a tachykinin peptide, which triggers intracellular signaling in the nervous and immune systems, as well as, other local and systemic events. The interaction between SP and its receptor, neurokinin-1 receptor (NK1R), results in major downstream cellular actions, which include changes in calcium fluxes, ERK, and p21-activated kinase phosphorylation and NFκB activation. Two naturally occurring variants of the NK1R, the full-length, 407 aa receptor (NK1R-F) and the truncated, 311 aa isoform (NK1R-T), mediate the actions of SP. Receptor truncation partially disrupts signaling motifs of the carboxyl tail, a critical site for mediating NK1R signaling, resulting in a "less-efficient" receptor. Although NK1R-F is the predominant isoform in the central and peripheral nervous systems, NK1R-T is expressed in several tissues and cells, which include monocytes, NK cells, and T-cells. The SP binding domain is not affected by truncation and this site is identical in both NK1R receptor isoforms. However, while cells expressing NK1R-F respond to nanomolar concentrations of SP, monocyte and macrophage activation, mediated through NK1R-T, requires micromolar concentrations of SP in order to elicit signaling responses. Elevated plasma levels of SP are associated with increased inflammatory responses and NK1R antagonists reduce inflammation and cytokine production in vivo. This mini review presents and discusses the novel hypothesis that the expression of NK1R-T on immune system cells prevents immune activation in a milieu, which usually contains low concentrations of SP and, thus, maintains immune homeostasis. In contrast, in the activated neuronal microenvironment, when SP levels reach the threshold at tissue sites, SP promotes immune activation and modulates monocyte/macrophage polarization.
P物质（SP）是一种速激肽肽，可触发神经和免疫系统以及其他局部和全身事件中的细胞内信号传导。SP与其受体神经激肽-1受体（NK1R）之间的相互作用会导致主要的下游细胞作用，包括钙通量、细胞外信号调节激酶（ERK）和p21激活激酶磷酸化以及核因子κB（NFκB）激活的变化。NK1R有两种天然存在的变体，全长407个氨基酸的受体（NK1R-F）和截短的311个氨基酸的同种型（NK1R-T），介导SP的作用。受体截短会部分破坏羧基末端的信号基序，而羧基末端是介导NK1R信号传导的关键位点，从而产生一种“效率较低”的受体。尽管NK1R-F是中枢和外周神经系统中的主要同种型，但NK1R-T在包括单核细胞、自然杀伤细胞和T细胞在内的多种组织和细胞中表达。SP结合域不受截短影响，并且在两种NK1R受体同种型中该位点是相同的。然而，虽然表达NK1R-F的细胞对纳摩尔浓度的SP有反应，但通过NK1R-T介导的单核细胞和巨噬细胞激活需要微摩尔浓度的SP才能引发信号反应。血浆中SP水平升高与炎症反应增加有关，NK1R拮抗剂可在体内减轻炎症和细胞因子产生。这篇小型综述提出并讨论了一个新的假设，即免疫系统细胞上NK1R-T的表达可在通常含有低浓度SP的环境中阻止免疫激活，从而维持免疫稳态。相反，在激活的神经元微环境中，当SP水平在组织部位达到阈值时，SP会促进免疫激活并调节单核细胞/巨噬细胞极化。
