Stress and Nasal Allergy: Corticotropin-Releasing Hormone Stimulates Mast Cell Degranulation and Proliferation in Human Nasal Mucosa.

Daisuke Tsuruta,Yukari Mizukami,Yukimi Kira,Mika Yamanaka-Takaichi,Kishiko Sunami,Yuichi Teranishi,Koji Sugawara,Ralf Paus

doi:10.3390/ijms22052773

Abstract

Psychological stress exacerbates mast cell (MC)-dependent inflammation, including nasal allergy, but the underlying mechanisms are not thoroughly understood. Because the key stress-mediating neurohormone, corticotropin-releasing hormone (CRH), induces human skin MC degranulation, we hypothesized that CRH may be a key player in stress-aggravated nasal allergy. In the current study, we probed this hypothesis in human nasal mucosa MCs (hM-MCs) in situ using nasal polyp organ culture and tested whether CRH is required for murine M-MC activation by perceived stress in vivo. CRH stimulation significantly increased the number of hM-MCs, stimulated both their degranulation and proliferation ex vivo, and increased stem cell factor (SCF) expression in human nasal mucosa epithelium. CRH also sensitized hM-MCs to further CRH stimulation and promoted a pro-inflammatory hM-MC phenotype. The CRH-induced increase in hM-MCs was mitigated by co-administration of CRH receptor type 1 (CRH-R1)-specific antagonist antalarmin, CRH-R1 small interfering RNA (siRNA), or SCF-neutralizing antibody. In vivo, restraint stress significantly increased the number and degranulation of murine M-MCs compared with sham-stressed mice. This effect was mitigated by intranasal antalarmin. Our data suggest that CRH is a major activator of hM-MC in nasal mucosa, in part via promoting SCF production, and that CRH-R1 antagonists such as antalarmin are promising candidate therapeutics for nasal mucosa neuroinflammation induced by perceived stress.

Highlights

These analyses demonstrate that corticotropin-releasing hormone (CRH) stimulates the degranulation and proliferation of unmanipulated, primary hM-mast cell (MC) within human nasal mucosa ex vivo in a CRH receptor type 1 (CRH-R1)- and stem cell factor (SCF)-dependent manner and suggest that stress-induced M-MC
Because we previously showed that CRH both increases the number and induces the degranulation of human skin MCs ex vivo [11], we were curious to learn how human nasal mucosa MCs (hM-MCs) would respond to the same dose and short-term incubation with CRH (10−7 M, 24 h) in human nasal polyp (NP) organ culture
We found no significant difference in MC apoptosis between vehicle control- and CRH-treated NPs using quantitative tryptase/terminal deoxynucleotidyl transferase (TdT)mediated dUTP nick end-labeling (TUNEL) double-immunofluorescence (Figure 3c)

Summary

Introduction

If the hypothesis that human airway mucosa MCs are activated under conditions of perceived stress via CRH/CRH-R stimulation is confirmed in situ, CRH and CRH-Rs would become promising novel targets for therapeutic interventions in a wide range of stress-aggravated, MC-dependent human airway diseases ranging from bronchial asthma via allergic rhinoconjunctivitis to nasal polyposis [44,45,46,47]. M-MCs (mM-MCs) and determined whether any effect is CRH-dependent by intranasally applying the selective CRH-R1 antagonist antalarmin [52] Taken together, these analyses demonstrate that CRH stimulates the degranulation and proliferation of unmanipulated, primary hM-MCs within human nasal mucosa ex vivo in a CRH-R1- and SCF-dependent manner and suggest that stress-induced M-MC degranulation in vivo is CRH-R1-dependent and can be inhibited with antalarmin

Results

CRH Increased SCF Expression in NP Epithelium In Situ

Discussion

Human Nasal Polyp Organ Culture

Toluidine Blue Histochemistry

CRH-R1 Gene Knockdown

Restraint Stress Mouse Model

Measurement of Plasma Corticosterone and CRH Levels

Findings

Statistical Analysis