Neuropeptide Y1 receptor & allergic inflammation
In a new Immunology & Cell Biology study, Laurence Macia and colleagues from the Garvan Institute of Medical Research, Darlinghurst, Australia, demonstrate that Neuropeptide Y (NPY) exacerbates allergic airway inﬂammation (AAI) in mice, via signaling through neuropeptide Y1 receptor.
Neuropeptide Y (NPY) is a 36 amino acid peptide discovered in 1982 by Kazuhiko Tatemoto, Mats Carlquist and Viktor Mutt.
NPY signals through 5 G-protein coupled receptors (Y1, Y2, Y4, Y5 and Y6), and functions in the brain for regulating feeding, memory, reproduction, hormone secretion from the anterior pituitary gland, temperature and circadian rhythms.
In the periphery, NPY is important for the regulation of gastrointestinal function and energy homeostasis. It cooperates with norepinephrine in regulation of vascular tone as a vasoconstrictor and an amplifier of norepinephrine-induced actions; but unlike norepinephrine, NPY is also a potent vascular mitogen and an angiogenic factor.
NPY also inﬂuences immune function especially via its Y1 receptor – B lymphocytes, CD4+ and CD8+ T lymphocytes, macrophages, dendritic cells, natural killers and mast cells express the Y1 receptor. In the presence of NPY, differentiated T helper (Th)1 cells produce less interferon-gamma, but Th2 cells express an increased IL-4 production. Thus, NPY might possess Th2-inducing properties. NPY has been implicated in intestinal disorders, hypertension, diabetes, congestive heart failure, feeding disorders and obesity, seizures, anxiety, and depression.
NPY is released from the sympathetic nerves after more intense and prolonged nerve activation and particularly during chronic stress. It is known that psychological stress may induce or facilitate allergic reactions and asthma, and serum levels of NPY are increased during asthma exacerbations. In addition, lung tissue is highly innervated with NPY-positive nerve ﬁbres; NPY exerts a signiﬁcant contractile effect on trachea and induces histamine secretion from mast cells.
In the new Immunology & Cell Biology study the authors found that the development of AAI was associated with elevated NPY expression in the lung and that mice lacking Y1 receptor signaling have signiﬁcantly reduced symptoms of AAI. In both NPY- and Y1-deﬁcient mice, eosinophilia in the bronchoalveolar ﬂuid and circulating immunoglobulin E were signiﬁcantly reduced, and these changes correlated with a blunting of the Th2 immune proﬁle that is characteristic for AAI.
According to the authors, these findings indicates that NPY signaling through Y1 receptors is critical for the regulation of the Th2 immune response necessary for AAI development. This may also suggest that targeting NPY signaling might be a promising strategy to improve AAI and potentially helpful for the treatment of asthma.
SOURCE: Immunol Cell Biol 2011, 89:882. doi: 10.1038/icb.2011.6. Epub 2011 Mar 8
A 2019 study by Naohiro Oda and colleagues published in the American Journal of Physiology-Lung Cellular and Molecular Physiology indicates that NPY contributes to allergen-induced airway hyperresponsiveness (AHR) and inflammation through accumulation of dendritic cells in the airway and promotion of the type 2 immune response.
In this study the authors investigated the role of NPY in allergen-induced AHR and inflammation in house dust mite (HDM) extract-challenged mice. In brief, mice were sensitized with HDM extract by intranasal instillation on days 0–2. The mice were subsequently challenged with HDM extract by intranasal instillation on days 14–17.
The authors also assessed NPY-deficient (NPY−/−) mice and the effects of treatment with an NPY receptor antagonist and showed that both approaches attenuated development of AHR, airway inflammation, and the accumulation of CD11c+ antigen-presenting cells (APCs) in the airway.
Of note, after sensitization and challenge, NPY-deficient mice showed significantly lower AHR than wild-type mice, and numbers of eosinophils and levels of type 2 cytokines [interleukin (IL)-4, IL-5, and IL-13] in bronchoalveolar lavage fluid were significantly lower. Type 2 cytokine production from splenic mononuclear cells of HDM-sensitized mice was also significantly lower in NPY-deficient mice.
The major finding of this study is that NPY helps, in fact, both systemic sensitization and local activation of Th2 cells, as well as the accumulation of CD11c+ APCs in the airways and migration of CD11c+ APCs to mediastinal lymph nodes (MLNs) following sensitization and challenge with HDM extract.
Thus, it appears that NPY contributes to to allergen-induced AHR and airway inflammation through two major mechanisms: the migration of DCs to regional lymph nodes, and, the promotion of the type 2 immune response.
Importantly, Naohiro Oda et al. also demonstrated for the first time that a Y1 receptor antagonist suppressed allergen-induced AHR and airway inflammation, which are important bronchial asthma phenotypes.
Thus, in conclusion, manipulating NPY may represent a novel therapeutic target to control allergic airway responses.