Neuropeptide Y – Dendritic Cells Migration – Th2 Polarization
NPY is a neurotransmitter released by the sympathetic nervous system along with norepinephrine (noradrenaline), and elevated NPY levels are detected in conditions of acute or chronic psychological stress as well as cold stress.
In recent years, elevated NPY levels have also been implicated in various inflammatory conditions such as asthma, atherosclerosis, rheumatoid arthritis, obesity and cancer, and several studies have suggested NPY as a major factor in the known link between stress and exacerbations of these diseases.
Neuropeptide Y has been shown to inhibit macrophage cytokine production and natural killer (NK) cell activity, while also stimulating the migration of monocytes, endothelial, polymorphonuclear and NK cells, and inducing a Th2 shift.
In the April 03, 2014 online issue of The FASEB Journal, Brigitta Buttari and colleagues from Istituto Superiore di Sanità, and the Institute of Neurobiology and Molecular Medicine, Italian National Research Council, Rome, Italy further characterize some pathways through which NPY impacts the immune system. More specifically, the authors examine the effect of NPY on DCs and their interactions with T cells.
The study finds that NPY is a potent inducer of chemotaxis, adhesion to endothelial cells, and transendothelial migration of human monocyte-derived immature DCs; and identifies that the binding to NPY-Y1R and subsequent ERK and p38 MAPK activation is a possible pathway mediating the chemotactic response.
Furthermore, the study also provides evidence that the NPY-stimulated DCs increase their interleukin (IL)-10 and IL-6 production, thus promoting differentiation of naïve T cells into a Th2 phenotype.
Thus, during an immune/inflammatory response NPY may exert pro-inflammatory effects through the recruitment of immature DCs, but it may exert anti-inflammatory effects by promoting a Th2 polarization.
These findings may also have clinical implications for the well-known stress-induced exacerbations of allergy/asthma and certain autoimmune and rheumatic diseases; or cold weather stress-aggravated rheumatic conditions and/or cardiovascular incidents.
Understanding the role and specific actions of NPY in inflammatory diseases can have major clinical implications and may stimulate future research to investigate the potential of NPY as a diagnostic or prognostic marker or therapeutic target.
Source: FASEB J, 2014, Apr 3. [Epub ahead of print], doi: 10.1096/fj.13-243485
Read more: fasebj.org
In a 2019 study Naohiro Oda et al. used NPY-deficient and wild-type mice. These animals were intranasally sensitized and challenged to house dust mite (HDM) extract. 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.
These authors provide eveidence that NPY contributes to both systemic sensitization and local activation of Th2 cells, as well as to the accumulation of CD11c+ APCs in the airways and migration of CD11c+ APCs to MLNs following sensitization and challenge with HDM extract. Thus, these data identify the important contribution of NPY to allergen-induced AHR and airway inflammation through migration of DCs to regional lymph nodes and promotion of the type 2 immune response.
Importantly, the authors 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, manipulating NPY represents a novel therapeutic target to control allergic airway responses.
A 2022 study by Elisabetta Profumo et al. indicates that NPY exerts a cytoprotective effect on human macrophages by preventing the expression of an inflammatory phenotype and stimulating anti-inflammatory functions, thus shifting human macrophages toward an anti-inflammatory M2-like phenotype. These authors also provide evidence that NPY effects on the M0 macrophage phenotype and functions are concomitant with the induction of autophagy and the activation of the p62/NRF2/HO-1 pathway.
The study suggests that the polarization of macrophages in the presence of NPY provides the capacity to restrain the inflammatory response induced by bacterial LPS, and that simultaneously enhances expression of the regulatory cytokine IL-10. The authors concluded that on the whole, NPY is able to shift the M1/M2 macrophage balance towards an anti-inflammatory profile, and to promote the activation of the NRF2–antioxidant pathway.
Cover Image Credit: Cover Image Credit: From Dendritic Cells by Ali Roghanian, University of Southampton Faculty of Medicine www.immunology.org/public-information/bitesized-immunology/cells/dendritic-cells