A fundamental bimodal role for neuropeptide Y1 receptor in the immune system

Abstract

Psychological conditions, including stress, compromise immune defenses. Although this concept is not novel, the molecular mechanism behind it remains unclear. Neuropeptide Y (NPY) in the central nervous system is a major regulator of numerous physiological functions, including stress. Postganglionic sympathetic nerves innervating lymphoid organs release NPY, which together with other peptides activate five Y receptors (Y1, Y2, Y4, Y5, and y6). Using Y1-deficient (Y1−/−) mice, we showed that Y1−/− T cells are hyperresponsive to activation and trigger severe colitis after transfer into lymphopenic mice. Thus, signaling through Y1 receptor on T cells inhibits T cell activation and controls the magnitude of T cell responses. Paradoxically, Y1−/− mice were resistant to T helper type 1 (Th1) cell–mediated inflammatory responses and showed reduced levels of the Th1 cell–promoting cytokine interleukin 12 and reduced interferon γ production. This defect was due to functionally impaired antigen-presenting cells (APCs), and consequently, Y1−/− mice had reduced numbers of effector T cells. These results demonstrate a fundamental bimodal role for the Y1 receptor in the immune system, serving as a strong negative regulator on T cells as well as a key activator of APC function. Our findings uncover a sophisticated molecular mechanism regulating immune cell functions that can lead to stress-induced immunosuppression.

Y1 signalling has a critical role in allergic airway inflammation

“…We have previously shown that lack of Y1 signalling in the DCs impaired their capacity to uptake the antigen and to efficiently stimulate the T cells. 10 Potentially, this effect of NPY on the DCs may be mediated by an autocrine process consistent with the expression of NPY in DCs. 16 During AAI, the possible inability of the DCs to properly mount an immune response might explain the protection seen in the Y1KO and NPYKO mice.…”

“…We have shown that lack of Y1 receptor signalling protected the mice against delayed type hypersensitivity suggesting that NPY has a key role in the control of inflammation. 10 Based on this evidence, we hypothesize that NPY may also have a critical role in AAI development. To test this hypothesis, we studied the immune response profile and the airway inflammation in mice lacking NPY as well as mice lacking the major Y-receptor, Y1, on immune cells during AAI development.…”

“…13 Moreover, NPY modulates the DC functionality, initiator of the Th2 orientation, ass lack of Y1 signalling impairs DC's capacity to induce an adaptive immune response. 10 Finally, like in the airway allergic reaction, the delayed type hypersensitivity model requires both a challenge and sensitization with the antigen, contributing to an exacerbated inflammatory response. We have shown that lack of Y1 receptor signalling protected the mice against delayed type hypersensitivity suggesting that NPY has a key role in the control of inflammation.…”

神经肽Y通过Y1受体激活PI3K通路促进RAW264.7细胞中TGF-β1 的产生 周江睿, 徐拯, 蒋春雷

“…Earlier studies indicated that Y1 -/-macrophages produced significantly less TNF-α than Y1 +/+ peritoneal macrophages in response to LPS; Y1 receptor antagonist was capable of inhibiting TNF-α secretion by normal LPS-activated peritoneal macrophages [8] .…”

“…NPY and Y1 receptor are expressed by many kinds of hemopoietic and immune cells such as T cells, B cells, monocytes and macrophages [7] . Recent findings point to a role of this neuropeptide in adaptive immunity: expression of Y1 receptor in dendritic cells is essential for antigen presenting cells (APC) function; and Y1 signaling plays a regulatory role in T cells, which will be hyper-responsive without Y1 [8] . Elevated serum level of NPY has also been detected in the patients with asthma and systemic lupus erythematosus [9] .…”