Endocannabinoids limit excessive mast cell maturation and activation in human skin

Koji Sugawara, Tamás Bíró, Daisuke Tsuruta, Balázs I. Tóth, Arno Kromminga, Nóra Zákány, Anne Zimmer, Wolfgang Funk, Bernhard F. Gibbs, Andreas Zimmer, Ralf Paus

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Background: Mast cells (MCs) crucially contribute to many inflammatory diseases. However, the physiological controls preventing excessive activities of MCs in human skin are incompletely understood. Objective: Since endocannabinoids are important neuroendocrine MC modifiers, we investigated how stimulation/inhibition of cannabinoid 1 (CB1) receptors affect the biology of human skin MCs in situ. Methods: This was investigated in the MC-rich connective tissue sheath of organ-cultured human scalp hair follicles by quantitative (immuno)histomorphometry, ultrastructural, and quantitative PCR techniques with the use of CB1 agonists or antagonists, CB1 knockdown, or CB1 knockout mice. Results: Kit+ MCs within the connective tissue sheath of human hair follicles express functional CB1 receptors, whose pharmacological blockade or gene silencing significantly stimulated both the degranulation and the maturation of MCs from resident progenitor cells in situ (ie, enhanced the number of tryptase+, FcεRIα, or chymase+ connective tissue sheath-MCs). This was, at least in part, stem cell factor-dependent. CB1 agonists counteracted the MC-activating effects of classical MC secretagogues. Similar phenomena were observed in CB1 knockout mice, attesting to the in vivo relevance of this novel MC-inhibitory mechanism. Conclusion: By using human hair follicle organ culture as an unconventional, but clinically relevant model system for studying the biology of MCs in situ, we show that normal skin MCs are tightly controlled by the endocannabinoid system. This limits excessive activation and maturation of MCs from resident progenitors via "tonic" CB1 stimulation by locally synthesized endocannabinoids. The excessive numbers and activation of MCs in allergic and other chronic inflammatory skin diseases may partially arise from resident intracutaneous MC progenitors, for example, because of insufficient CB1 stimulation. Therefore, CB1 stimulation is a promising strategy for the future management of allergy and MC-dependent skin diseases.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
Volume129
Issue number3
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

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Endocannabinoids
Mast Cells
Skin
Cannabinoids
Hair Follicle
Connective Tissue
Cannabinoid Receptor Agonists
Cannabinoid Receptors
Skin Diseases
Knockout Mice
Cannabinoid Receptor Antagonists
Chymases
Tryptases
Neuroendocrine Cells
Stem Cell Factor
Systems Biology
Organ Culture Techniques
Gene Silencing

Keywords

  • cannabinoid receptor
  • Endocannabinoid
  • hair follicle
  • mast cell
  • skin
  • stem cell factor
  • tryptase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Endocannabinoids limit excessive mast cell maturation and activation in human skin. / Sugawara, Koji; Bíró, Tamás; Tsuruta, Daisuke; Tóth, Balázs I.; Kromminga, Arno; Zákány, Nóra; Zimmer, Anne; Funk, Wolfgang; Gibbs, Bernhard F.; Zimmer, Andreas; Paus, Ralf.

In: Journal of Allergy and Clinical Immunology, Vol. 129, No. 3, 01.01.2012.

Research output: Contribution to journalArticle

Sugawara, K, Bíró, T, Tsuruta, D, Tóth, BI, Kromminga, A, Zákány, N, Zimmer, A, Funk, W, Gibbs, BF, Zimmer, A & Paus, R 2012, 'Endocannabinoids limit excessive mast cell maturation and activation in human skin', Journal of Allergy and Clinical Immunology, vol. 129, no. 3. https://doi.org/10.1016/j.jaci.2011.11.009
Sugawara, Koji ; Bíró, Tamás ; Tsuruta, Daisuke ; Tóth, Balázs I. ; Kromminga, Arno ; Zákány, Nóra ; Zimmer, Anne ; Funk, Wolfgang ; Gibbs, Bernhard F. ; Zimmer, Andreas ; Paus, Ralf. / Endocannabinoids limit excessive mast cell maturation and activation in human skin. In: Journal of Allergy and Clinical Immunology. 2012 ; Vol. 129, No. 3.
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