Neuromedin U Induces Activation of Peripheral Group 2 Innate Lymphoid Cells through the ERK Pathway in Allergic Rhinitis Patients. 2023

Xueping Qi, and Hedi Zhuo, and Yanjie Wang, and Fanggang Ren, and Jinmei Xue, and Yunfang An, and Changqing Zhao
Shanxi Medical University, Taiyuan, China, qixueping214@163.com.

In allergic diseases, group 2 innate lymphoid cells (ILC2s) play critical roles. Neuromedin U (NMU), a highly conserved multifunctional neuropeptide, is secreted by cholinergic neurons and involved in asthma pathogenesis by amplifying lung inflammation driven by ILC2s. However, the precise effects of NMU on ILC2s in allergic rhinitis (AR) and related diseases remain unclear. A total of 15 patients with persistent AR and 8 healthy controls (HCs) were enrolled in the study. Visual analog scale (VAS) scores are used to assess the severity of clinical symptoms in AR patients. The percentages of ILC2s in peripheral blood mononuclear cells (PBMCs) were enumerated using flow cytometry. The soluble or intracellular cytokines (IL-5 and IL-13) in PBMCs or sorted ILC2s were assessed in response to various stimuli with IL-33, NMU, IL-33 combined with extracellular signal-related kinase (ERK) inhibitor or NMU combined with ERK inhibitor in the presence of IL-2. We confirmed the proportion of circulating ILC2s was significantly higher in AR patients than in HCs. ILC2s levels were found to be positively related to VAS scores. We also discovered that the release of IL-5 and IL-13 in AR patients' PBMCs stimulated by NMU (p < 0.0001 and p < 0.0001, respectively) or IL-33 (p = 0.002; p = 0.044, respectively) was significantly higher than in HCs. In AR patients, NMU stimulated PBMCs or ILC2s to generate greater inflammatory factors IL-5 and IL-13 compared to IL-33. Furthermore, we observed that NMU-promoted ILC2s activation and proliferation functions were restricted when the ERK pathway was inhibited. NMU effectively activated ILC2s in AR patients to produce Th2-type cytokines, and this activation can be prevented by ERK pathway inhibitors. Our findings shed new light on the neuro-immune mechanism of AR and offer new insights into its prevention and treatment.

UI MeSH Term Description Entries
D007113 Immunity, Innate The capacity of a normal organism to remain unaffected by microorganisms and their toxins. It results from the presence of naturally occurring ANTI-INFECTIVE AGENTS, constitutional factors such as BODY TEMPERATURE and immediate acting immune cells such as NATURAL KILLER CELLS. Immunity, Native,Immunity, Natural,Immunity, Non-Specific,Resistance, Natural,Innate Immune Response,Innate Immunity,Immune Response, Innate,Immune Responses, Innate,Immunity, Non Specific,Innate Immune Responses,Native Immunity,Natural Immunity,Natural Resistance,Non-Specific Immunity
D007963 Leukocytes, Mononuclear Mature LYMPHOCYTES and MONOCYTES transported by the blood to the body's extravascular space. They are morphologically distinguishable from mature granulocytic leukocytes by their large, non-lobed nuclei and lack of coarse, heavily stained cytoplasmic granules. Mononuclear Leukocyte,Mononuclear Leukocytes,PBMC Peripheral Blood Mononuclear Cells,Peripheral Blood Human Mononuclear Cells,Peripheral Blood Mononuclear Cell,Peripheral Blood Mononuclear Cells,Leukocyte, Mononuclear
D008214 Lymphocytes White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each), or NATURAL KILLER CELLS. Lymphoid Cells,Cell, Lymphoid,Cells, Lymphoid,Lymphocyte,Lymphoid Cell
D009479 Neuropeptides Peptides released by NEURONS as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. Neuropeptide
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067596 Interleukin-33 A member of the INTERLEUKIN-1 protein family involved in the maturation of TH2 CELLS and the activation of MAST CELLS; BASOPHILS; EOSINOPHILS and NK CELLS. It is also produced by ENDOTHELIAL CELLS; EPITHELIAL CELLS and FIBROBLASTS; where it can function as an alarmin to modulate immune and inflammatory responses to tissue damage. IL-33,IL33,Interleukin 33
D015848 Interleukin-5 A cytokine that promotes differentiation and activation of EOSINOPHILS. It also triggers activated B-LYMPHOCYTES to differentiate into IMMUNOGLOBULIN-secreting cells. B-Cell Growth Factor-II,Eosinophil Differentiation Factor,IL-5,T-Cell Replacing Factor,BCGF-II,Differentiation Factor, Eosinophil,IL5,T-Cell-Replacing Factor,B Cell Growth Factor II,Interleukin 5,Replacing Factor, T-Cell,T Cell Replacing Factor
D016207 Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Cytokine
D018793 Interleukin-13 A cytokine synthesized by T-LYMPHOCYTES that produces proliferation, immunoglobulin isotype switching, and immunoglobulin production by immature B-LYMPHOCYTES. It appears to play a role in regulating inflammatory and immune responses. IL-13,IL 13,IL13,Interleukin 13
D020935 MAP Kinase Signaling System An intracellular signaling system involving the mitogen-activated protein kinase cascades (three-membered protein kinase cascades). Various upstream activators, which act in response to extracellular stimuli, trigger the cascades by activating the first member of a cascade, MAP KINASE KINASE KINASES; (MAPKKKs). Activated MAPKKKs phosphorylate MITOGEN-ACTIVATED PROTEIN KINASE KINASES which in turn phosphorylate the MITOGEN-ACTIVATED PROTEIN KINASES; (MAPKs). The MAPKs then act on various downstream targets to affect gene expression. In mammals, there are several distinct MAP kinase pathways including the ERK (extracellular signal-regulated kinase) pathway, the SAPK/JNK (stress-activated protein kinase/c-jun kinase) pathway, and the p38 kinase pathway. There is some sharing of components among the pathways depending on which stimulus originates activation of the cascade. MAP Kinase Cascade,MAP Kinase Module,MAP Kinase Signaling Cascade,MAP Kinase Signaling Pathway,MAP Kinase Signaling Pathways,ERK Pathway,ERK Signal Tranduction Pathway,ERK1 and ERK2 Pathway,ERK1-2 Pathway,JNK Pathway,JNK Signaling Pathway,MAP Kinase Modules,MAP Kinase Signaling Cascades,MEK-ERK Pathway,p38 Kinase Pathway,p38 Kinase Signaling Pathway,Cascade, MAP Kinase,ERK Pathways,ERK1 2 Pathway,ERK1-2 Pathways,JNK Pathways,JNK Signaling Pathways,Kinase Cascade, MAP,Kinase Pathway, p38,Kinase Pathways, p38,MAP Kinase Cascades,MEK ERK Pathway,MEK-ERK Pathways,Module, MAP Kinase,Pathway, ERK,Pathway, ERK1-2,Pathway, JNK,Pathway, JNK Signaling,Pathway, MEK-ERK,Pathway, p38 Kinase,Pathways, ERK,Pathways, ERK1-2,Pathways, JNK,Pathways, JNK Signaling,Pathways, MEK-ERK,Pathways, p38 Kinase,Signaling Pathway, JNK,Signaling Pathways, JNK,p38 Kinase Pathways

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