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Corticotropin-releasing hormone stimulates mast cell degranulation and proliferation in human nasal mucosa
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  • Mika Yamanaka-Takaichi,
  • Yukari Mizukami,
  • Koji Sugawara,
  • Kishiko Sunami,
  • Yuichi Teranishi,
  • Yukimi Kira,
  • Ralf Paus,
  • Daisuke Tsuruta
Mika Yamanaka-Takaichi
Osaka City University Graduate School of Medicine School of Medicine
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Yukari Mizukami
Osaka City University Graduate School of Medicine School of Medicine
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Koji Sugawara
Osaka City University Graduate School of Medicine School of Medicine

Corresponding Author:[email protected]

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Kishiko Sunami
Osaka City University Graduate School of Medicine School of Medicine
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Yuichi Teranishi
Osaka City University Graduate School of Medicine School of Medicine
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Yukimi Kira
Osaka City University Graduate School of Medicine School of Medicine
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Ralf Paus
University of Miami Miller School of Medicine
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Daisuke Tsuruta
Osaka City University Graduate School of Medicine School of Medicine
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Abstract

Background: Psychological stress exacerbates mast cell (MC)-dependent inflammation, including nasal allergy, but the underlying mechanisms are not well 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. The current study probes this hypothesis in human nasal mucosa MCs (hM-MCs) in situ, using nasal polyp organ culture, and tests whether CRH is required for murine M-MC activation by perceived stress in vivo. Methods: Organ-cultured nasal polyps were used as a surrogate tissue for human upper airway mucosa and stimulated with CRH. In addition to quantitative immunohistomorphometry and transmission electron microscopy, we investigated whether perceived (restraint) stress activates murine M-MCs in vivo and whether this is CRH-dependent. Results: CRH stimulation significantly increased the number of hM-MCs, stimulated both their degranulation and proliferation ex vivo, and increased SCF expression in human nasal mucosa epithelium compared to controls. 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 abrogated by co-administration of CRH-R1 specific antagonist antalarmin, CRH-R1 siRNA, or SCF-neutralizing antibody. In vivo, both acute and chronic restraint stress significantly increased the number and degranulation of murine M-MCs compared to sham-stressed mice. This effect was abrogated by intranasal antalarmin. Conclusion: CRH is a major activator of hM-MC in nasal mucosa, in part via promoting SCF production, and CRH-R1 antagonists like antalarmin are promising candidate therapeutics for nasal mucosa neuroinflammation induced by perceived stress.