Focus on the role of substance P in chronic urticaria

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Abstract

Background

Emerging data have strengthened the importance of substance P (SP) as a proinflammatory mediator in human pathology. A role for SP in the pathogenesis of urticaria has long been hypothesized.

Methods

Literature data regarding the possible role of SP in chronic urticaria/chronic spontaneous urticaria (CSU) have been reviewed and summarized in this manuscript. This review is based on pertinent articles that were retrieved by a selective literature search in the PubMed database. Articles in English published up to July 2018 were taken into consideration.

Results

Recent studies in patients with CSU have demonstrated that circulating levels of SP are significantly elevated, in correlation with disease severity, and that SP-positive basophils are upregulated. SP has been shown to trigger degranulation in basophils derived from CSU patients. Moreover, SP can be involved in pseudoallergic reactions and may act as a histamine-releasing factor in a subset of patients with CSU. Current evidence suggests that the biological activity of SP can be exerted not only through the conventional NK-1 receptor but also through the recently identified Mas-related G protein-coupled receptors. MRGPRX2 can cause mast cell activation and has been found to be upregulated in the skin of patients with severe chronic urticaria.

Conclusions

Many findings seem to support the pathogenic involvement of SP in chronic urticaria/CSU. However, further studies are necessary to elucidate the role of SP as a mediator in CSU pathogenesis and a potential new therapeutic target.

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Most cited references 36

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Identification of a mast cell specific receptor crucial for pseudo-allergic drug reactions

Benjamin McNeil, Priyanka Pundir, Sonya Meeker … (2014)

Mast cells are primary effectors in allergic reactions, and may have significant roles in diseases by secreting histamine and various inflammatory and immunomodulatory substances 1,2 . While classically they are activated by IgE antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions 1,3 . Roles for these substances in pathology have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, MrgprB2, the orthologue of the human G-protein coupled receptor (GPCR) MrgprX2. Secretagogue-induced histamine release, inflammation, and airway contraction are abolished in MrgprB2 null mutant mice. Further, we show that most classes of FDA-approved peptidergic drugs associated with allergic-type injection-site reactions also activate MrgprB2 and MrgprX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that MrgprB2 and MrgprX2 are targets of many small molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice, and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MrgprX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

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The role of substance P in inflammatory disease.

Terence M. O'Connor, Joseph O'Connell, Darren O'Brien … (2004)

The diffuse neuroendocrine system consists of specialised endocrine cells and peptidergic nerves and is present in all organs of the body. Substance P (SP) is secreted by nerves and inflammatory cells such as macrophages, eosinophils, lymphocytes, and dendritic cells and acts by binding to the neurokinin-1 receptor (NK-1R). SP has proinflammatory effects in immune and epithelial cells and participates in inflammatory diseases of the respiratory, gastrointestinal, and musculoskeletal systems. Many substances induce neuropeptide release from sensory nerves in the lung, including allergen, histamine, prostaglandins, and leukotrienes. Patients with asthma are hyperresponsive to SP and NK-1R expression is increased in their bronchi. Neurogenic inflammation also participates in virus-associated respiratory infection, non-productive cough, allergic rhinitis, and sarcoidosis. SP regulates smooth muscle contractility, epithelial ion transport, vascular permeability, and immune function in the gastrointestinal tract. Elevated levels of SP and upregulated NK-1R expression have been reported in the rectum and colon of patients with inflammatory bowel disease (IBD), and correlate with disease activity. Increased levels of SP are found in the synovial fluid and serum of patients with rheumatoid arthritis (RA) and NK-1R mRNA is upregulated in RA synoviocytes. Glucocorticoids may attenuate neurogenic inflammation by decreasing NK-1R expression in epithelial and inflammatory cells and increasing production of neutral endopeptidase (NEP), an enzyme that degrades SP. Preventing the proinflammatory effects of SP using tachykinin receptor antagonists may have therapeutic potential in inflammatory diseases such as asthma, sarcoidosis, chronic bronchitis, IBD, and RA. In this paper, we review the role that SP plays in inflammatory disease. Copyright 2004 Wiley-Liss, Inc.

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Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria.

Daisuke Fujisawa, Jun-ichi Kashiwakura, Hirohito Kita … (2014)

Wheal reactions to intradermally injected neuropeptides, such as substance P (SP) and vasoactive intestinal peptide, are significantly larger and longer lasting in patients with chronic urticaria (CU) than in nonatopic control (NC) subjects. Mas-related gene X2 (MrgX2) has been identified as a receptor for basic neuropeptides, such as SP and vasoactive intestinal peptide. Mast cell (MC) responsiveness to eosinophil mediators contributes to the late-phase reaction of allergy.

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Author and article information

Contributors

Gino A. Vena: ginovena@gmail.com

Nicoletta Cassano: nicoletta.cassano@yahoo.com

E. Di Leo: +39 3921037176 , elisabettadileo71@libero.it

G. F. Calogiuri: gf.calogiuri@libero.it

Eustachio Nettis: ambulatorio.allergologia@uniba.it

Journal

Journal ID (nlm-ta): Clin Mol Allergy

Journal ID (iso-abbrev): Clin Mol Allergy

Title: Clinical and Molecular Allergy : CMA

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-7961

Publication date (Electronic): 19 November 2018

Publication date PMC-release: 19 November 2018

Publication date Collection: 2018

Volume: 16

Electronic Location Identifier: 24

Affiliations

[1 ]Dermatology and Venereology Private Practice, Bari, Barletta, Italy

[2 ]Section of Allergy and Clinical Immunology, Unit of Internal Medicine, “F. Miulli” Hospital, Acquaviva delle Fonti, BA Italy

[3 ]Pneumology Department, Sacro Cuore Hospital, Gallipoli, Lecce Italy

[4 ]ISNI 0000 0001 0120 3326, GRID grid.7644.1, Department of Emergency and Organ Transplantation, School and Chair of Allergology and Clinical Immunology, , University of Bari-Aldo Moro, ; Bari, Italy

Article

Publisher ID: 101

DOI: 10.1186/s12948-018-0101-z

PMC ID: 6240950

PubMed ID: 30473632

SO-VID: 8de4c803-d4a1-4854-a4b7-482dea7e3747

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 30 August 2018

Date accepted : 3 November 2018

Custom metadata

ScienceOpen disciplines: Immunology

Keywords: substance p,chronic urticaria,chronic spontaneous urticaria,neuropeptides,mast cells,basophils

Data availability:

ScienceOpen disciplines: Immunology

Keywords: substance p, chronic urticaria, chronic spontaneous urticaria, neuropeptides, mast cells, basophils

Focus on the role of substance P in chronic urticaria

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Abstract

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Most cited references 36

Identification of a mast cell specific receptor crucial for pseudo-allergic drug reactions

The role of substance P in inflammatory disease.

Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria.

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