Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses.

Abstract

BACKGROUND:

Efficient development of atopic diseases requires interactions between allergen and adjuvant to initiate and amplify the underlying inflammatory responses. Substance P (SP) and hemokinin-1 (HK-1) are neuropeptides that signal through the neurokinin-1 receptor (NK1R) to promote inflammation. Mast cells initiate the symptoms and tissue effects of atopic disorders, secreting TNF and IL-6 after FcεRI cross-linking by antigen-IgE complexes (FcεRI-activated mast cells [FcεRI-MCs]). Additionally, MCs express the NK1R, suggesting an adjuvant role for NK1R agonists in FcεRI-MC-mediated pathologies; however, in-depth research addressing this relevant aspect of MC biology is lacking.

OBJECTIVE:

We sought to investigate the effect of NK1R signaling and the individual roles of SP and HK-1 as potential adjuvants for FcεRI-MC-mediated allergic disorders.

METHODS:

Bone marrow-derived mast cells (BMMCs) from C57BL/6 wild-type (WT) or NK1R(-/-) mice were used to investigate the effects of NK1R signaling on FcεRI-MCs. BMMCs generated from Tac1(-/-) mice or after culture with Tac4 small interfering RNA were used to address the adjuvancy of SP and HK-1. WT, NK1R(-/-), and c-Kit(W-sh/W-sh) mice reconstituted with WT or NK1R(-/-) BMMCs were used to evaluate NK1R signaling on FcεRI-MC-mediated passive local and systemic anaphylaxis and on airway inflammation.

RESULTS:

FcεRI-activated MCs upregulated NK1R and HK-1 transcripts and protein synthesis, without modifying SP expression. In a positive signaling loop HK-1 promoted TNF and IL-6 secretion by MC degranulation and protein synthesis, the latter through the phosphoinositide 3-kinase/Akt/nuclear factor κB pathways. In vivo NK1R signaling was necessary for the development of passive local and systemic anaphylaxis and airway inflammation.

CONCLUSIONS:

FcεRI stimulation of MCs promotes autocrine secretion of HK-1, which signals through NK1R to provide adjuvancy for efficient development of FcεRI-MC-mediated disorders.

• Authors: Tina L Sumpter, Chin H Ho, Anna R Pleet, Olga A Tkacheva, William J Shufesky, Darling M Rojas-Canales, Adrian E Morelli, Adriana T Larregina
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 135 Issue 4 Pg. 1019-1030.e8 (Apr 2015) ISSN: 1097-6825 [Electronic] United States
• PMID: 25201259 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Interleukin-6
• Receptors, IgE
• Receptors, Neurokinin-1
• Tachykinins
• Tumor Necrosis Factors
• hemokinin-1
• Immunoglobulin E

Topics

• Anaphylaxis (immunology, metabolism)
• Animals
• Autocrine Communication
• Disease Models, Animal
• Female
• Immunoglobulin E (immunology)
• Inflammation (immunology, metabolism)
• Interleukin-6 (biosynthesis)
• Lung (immunology, metabolism, pathology)
• Mast Cells (immunology, metabolism)
• Mice
• Mice, Knockout
• Receptors, IgE (metabolism)
• Receptors, Neurokinin-1 (metabolism)
• Signal Transduction
• Tachykinins (metabolism)
• Tumor Necrosis Factors (biosynthesis)