Trends in Immunology
Volume 27, Issue 4, April 2006, Pages 164-167
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A neuropeptide in immune-mediated inflammation, Y?

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Disturbances in crosstalk between the immune system and the sympathetic nervous system (SNS) can contribute to the pathogenesis of Th1-mediated autoimmunity. Recent studies indicate that neuropeptide Y (NPY) has a major role in the regulation of Th1 responses. The precise role of NPY has been an enigma, but a recent study provides a breakthrough, demonstrating that NPY has a bimodal role as a negative regulator of T cells and an activator of antigen-presenting cell function.

Section snippets

Neuropeptide Y – an interface between nervous and immune systems

Despite decades of evidence for bidirectional communication between the nervous system and the immune system 1, 2, the fields of neuroscience and immunology have evolved separately. Alterations in the sympathetic nervous system (SNS) are associated with certain inflammatory autoimmune diseases, such as multiple sclerosis (MS) [3] and rheumatoid arthritis (RA) [4]. Catecholamines, the major category of sympathetic neurotransmitter that have been shown to modulate some T-cell responses, have been

NPY-deficiency promotes Th1-mediated responses

Several immunomodulatory properties are attributed to Y1 signaling [7]. Wheway et al. [10] observed that Y1-deficient mice had reduced numbers of B cells, a defect in isotype switching to IgG2a (normally associated with Th1 responses) and increased numbers of naïve T cells, confirming the importance of Y1 in immune functions. Indeed, they observed that Y1-deficient mice were resistant to dextran sulfate sodium (DSS)-induced colitis and developed reduced delayed-type hypersensitivity (DTH) to

The bimodal role of NPY on T-cell regulation and APC activation

Wheway et al. [10] observed that Y1-deficient T cells in vitro showed hyperproliferation in response to anti-CD3 stimulation. In mixed leukocyte reactions (MLRs), NPY addition suppressed proliferation by wild-type T cells. Although previous data have indicated that Y1 is the principal receptor for NPY-mediated T-cell activity, testing NPY on Y1-deficient T cells (a negative control if NPY activity on T cells is mediated only through Y1) could have addressed whether NPY influences T-cell

Perspectives

NPY–Y1 is one of an increasing number of molecular pathways initially characterized in the nervous system that were subsequently discovered to interface with the immune system and participate in immune regulation 1, 2. Semaphorins, originally identified as guidance molecules for axonal development, are now recognized as molecules involved in T-cell activation. The semaphorin Sema4A, expressed on APCs, participates in the immunological synapse, serving as a co-stimulatory molecule during Th1

Concluding remarks

The identification of the proinflammatory effects of NPY on APCs might reduce interest in the potential application of NPY and NPY analogs in the treatment of Th1-mediated autoimmune conditions, for example, MS and RA. In this regard, although NPY prevented the induction of acute EAE by inhibiting Th1 responses, it could not reverse chronic EAE, a phase of the disease in which activated macrophages might predominate in CNS damage [15]. In addition, the findings that Y1-deficient mice (lacking

Acknowledgements

We thank Anthony Slavin and Patricia Nelson for helpful discussions. T.P. is a fellow of the National Multiple Sclerosis Society (NMSS). L.S. is supported by grants from the NIH, NMSS and the Phil N. Allen Trust. S.S.Z. is supported by grants from the NIH, NMSS, The Dana Foundation and The Maisin Foundation.

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