Endocannabinoids limit excessive mast cell maturation and activation in human skin.
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.


CONCLUSIONS
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.
Department of Dermatology, University of Lübeck, Lübeck, Germany; Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Koji
K
Sugawara
Tamás
T
Bíró
Daisuke
D
Tsuruta
Balázs I
BI
Tóth
Arno
A
Kromminga
Nóra
N
Zákány
Anne
A
Zimmer
Wolfgang
W
Funk
Bernhard F
BF
Gibbs
Andreas
A
Zimmer
Ralf
R
Paus
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000276:immunology / Q000378:metabolism*; D015550:Cell Degranulation / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D063388:Endocannabinoids; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012826:Silicone Elastomers / Q000494:pharmacology; D012867:Skin / Q000473:pathology; D019089:Stem Cell Factor / Q000494:pharmacology
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; D012826:Silicone Elastomers; D019089:Stem Cell Factor; C119325:arachidonyl-2-chloroethylamide; C006194:aminoethyl-aminopropyl-trimethoxysilane; D019009:Proto-Oncogene Proteins c-kit