Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

Abstract

Neuropeptide Y (NPY), which is widely distributed in the nervous system, is involved in regulating a variety of biological processes, including food intake, energy metabolism, and emotional expression. However, emerging evidence points to NPY also as a critical transmitter between the nervous system and immune system, as well as a mediator produced and released by immune cells. In vivo and in vitro studies based on gene-editing techniques and specific NPY receptor agonists and antagonists have demonstrated that NPY is responsible for multifarious direct modulations on immune cells by acting on NPY receptors. Moreover, via the central or peripheral nervous system, NPY is closely connected to body temperature regulation, obesity development, glucose metabolism, and emotional expression, which are all immunomodulatory factors for the immune system. In this review, we focus on the direct role of NPY in immune cells and particularly discuss its indirect impact on the immune response.

Keywords: body temperature; diabetes; emotion; immune cells; immunomodulatory; neuropeptide Y; obesity.

Figure 1

The agonists and antagonists of Y receptors. (A) NPY and PYY are processed into different ligands. Although these ligands have a similar amino acid composition to NPY/PYY, when the two amino acid residues of NPY/PYY are replaced or truncated, it significantly changes their affinity for different Y receptor subtypes. (B) The most commonly used agonists and antagonists specific for different Y receptor subtypes. NPY, neuropeptide Y; PYY, peptide YY; Tyr, Tyrosine; Leu, Leucine; Pro, Proline; Ala, Alanine; Aib, 2-aminoisobutyric acid.

Figure 2

NPY directly regulates immune cells. NPY of the immune system derived from the secretion of the sympathetic nervous system, tissue structure cells, and immune cells. NPY plays multiple roles in immune cells, including via Y1R inhibiting activation and regulation of proliferation, differentiation, and cytokine secretion; via Y1R/Y2R/Y5R mediating phagocytosis and migration. Among these, Y1R has a bimodal effect on the immune system, showing both anti-inflammatory properties and specific pro-inflammatory effects. In addition, the Y1R mainly mediates the promotion of NPY, while the Y2/Y5 receptor mediates the inhibition of NPY. Therefore, the interaction of Y1R and Y2/Y5R is involved in the regulation of immune cells. In this figure, NPY receptor symbols on different immune cells symbolize their involvement in the diverse functional regulation of NPY. NK, natural killer; NPY, neuropeptide Y; SNS, sympathetic nervous system.

Figure 3

NPY indirectly regulates the immune response. NPY regulates thermoregulation, obesity, and development of diabetes by controlling the vasomotor of the skin, thermogenesis of BAT, fat storage in WAT, food intake, insulin secretion, and insulin resistance. Moreover, NPY plays anti-anxiety and anti-depression roles to transform emotional expression. Interestingly, this regulation by NPY profoundly impacts the immune response. BAT, brown adipose tissue; NPY, neuropeptide Y; WAT, white adipose tissue.