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Neuropeptide Substance P and the Immune Response

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Substance P is a peptide mainly secreted by neurons and is involved in many biological processes, including nociception and inflammation. Animal models have provided insights into the biology of this peptide and offered compelling evidence for the importance of substance P in cell-to-cell communication by either paracrine or endocrine signaling. Substance P mediates interactions between neurons and immune cells, with nerve-derived substance P modulating immune cell proliferation rates and cytokine production. Intriguingly, some immune cells have also been found to secrete substance P, which hints at an integral role of substance P in the immune response. These communications play important functional roles in immunity including mobilization, proliferation and modulation of the activity of immune cells. This review summarizes current knowledge of substance P and its receptors, as well as its physiological and pathological roles. We focus on recent developments in the immunobiology of substance P and discuss the clinical implications of its ability to modulate the immune response.
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REVIEW
Neuropeptide substance P and the immune response
Alireza Mashaghi
1
Anna Marmalidou
1
Mohsen Tehrani
1
Peter M. Grace
2
Charalabos Pothoulakis
3
Reza Dana
1
Received: 28 January 2016 / Revised: 25 May 2016 / Accepted: 9 June 2016 / Published online: 17 June 2016
ÓSpringer International Publishing 2016
Abstract Substance P is a peptide mainly secreted by neu-
rons and is involved in many biological processes, including
nociception and inflammation. Animal models have pro-
vided insights into the biology of this peptide and offered
compelling evidence for the importance of substance P in
cell-to-cell communication by either paracrine or endocrine
signaling. Substance P mediates interactions between neu-
rons and immune cells, with nerve-derived substance P
modulating immune cell proliferation rates and cytokine
production. Intriguingly, some immune cells have also been
found to secrete substance P, which hints at an integral role of
substance P in the immune response. These communications
play important functional roles in immunity including
mobilization, proliferation and modulation of the activity of
immune cells. This review summarizes current knowledge of
substance P and its receptors, as well as its physiological and
pathological roles. We focus on recent developments in the
immunobiology of substance P and discuss the clinical
implications of its ability to modulate the immune response.
Keywords Immune regulation Neuropeptides
Cell-to-cell communication Signaling Cellular dynamics
Introduction
Substance P (SP) is a highly conserved peptide that was
originally discovered in 1931 by Von Euler and Gaddum in
the equine brain and gut extracts—distinct from acetyl-
choline—capable of inducing hypotension and muscle
contraction [1]. This substance was purified and dried in
powder form (hence the name substance P) [2]; highly
conserved homologs were later identified in mice, rabbits,
and humans (Fig. 1a). SP is encoded by the TAC1 gene
(located on chromosome 7 in humans) and is a member of
the tachykinin peptide hormone family [3] (Fig. 1b); the
family also contains three other neuropeptides, also enco-
ded by TAC1, namely neurokinin A, neuropeptide K, and
neuropeptide c[4,5]. SP is expressed by many cell types
including neurons [69], astrocytes [10,11], microglia
[12], epithelial cells [13], and endothelial cells [14].
Immune cells, such as T cells [15], macrophages [16,17],
dendritic cells [18], or eosinophils [19] also display sig-
nificant levels of SP expression [16,15,20]. SP is also
expressed by some stem cells and progenitor cells [21],
including immunomodulatory mesenchymal stem cells
(MSC) [22]. Such widespread expression of SP in diverse
cell types may suggest its participation in a wide variety of
physiological and pathophysiological functions, by acti-
vating a multitude of signaling pathways.
Structure
The physicochemical properties of substance P underlie its
function. The SP peptide comprises 11 amino acids
(RPKPQQFFGLM-NH2) [23] with a net positive charge at
physiologic pH. Positively charged residues are located on
the N-terminus, while the C-terminus contains hydrophobic
A. Mashaghi and A. Marmalidou contributed equally to this work.
&Reza Dana
reza_dana@meei.harvard.edu
1
Schepens Eye Research Institute, Massachusetts Eye and Ear
Infirmary, Harvard Medical School, Boston, MA 02114, USA
2
Department of Psychology and Neuroscience, Center for
Neuroscience, University of Colorado, Boulder, CO 80309,
USA
3
Division of Digestive Diseases, David Geffen School of
Medicine, Inflammatory Bowel Disease Center, University of
California, Los Angeles, Los Angeles, CA, USA
Cell. Mol. Life Sci. (2016) 73:4249–4264
DOI 10.1007/s00018-016-2293-z Cellular and Molecular Life Sciences
123
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... However, little work has been done in the area of basic research work about the suitability of SP as a biomarker for pain in cattle so far. Studies in human medicine showed that SP plays a role in the activation of the immune system, chemotaxis of granulocytes, and migration of cells to the location of inflamed tissue [16,75]. SP concentrations increase during an inflammatory process [16,75,76]. ...
... Studies in human medicine showed that SP plays a role in the activation of the immune system, chemotaxis of granulocytes, and migration of cells to the location of inflamed tissue [16,75]. SP concentrations increase during an inflammatory process [16,75,76]. The same can be said for conditions of emotional stress [77]. ...
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