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.
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 humanscalp 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 insufficientCB1 stimulation. Therefore, CB1 stimulation is a promising strategy for the future management of allergy and MC-dependent skin diseases.
Authors: Alexandra C Kendall; Suzanne M Pilkington; Karen A Massey; Gary Sassano; Lesley E Rhodes; Anna Nicolaou Journal: J Invest Dermatol Date: 2015-02-10 Impact factor: 8.551
Authors: Irene M Wohlman; Gabriella M Composto; Diane E Heck; Ned D Heindel; C Jeffrey Lacey; Christophe D Guillon; Robert P Casillas; Claire R Croutch; Donald R Gerecke; Debra L Laskin; Laurie B Joseph; Jeffrey D Laskin Journal: Toxicol Appl Pharmacol Date: 2016-04-26 Impact factor: 4.219
Authors: Mauro Maccarrone; Itai Bab; Tamás Bíró; Guy A Cabral; Sudhansu K Dey; Vincenzo Di Marzo; Justin C Konje; George Kunos; Raphael Mechoulam; Pal Pacher; Keith A Sharkey; Andreas Zimmer Journal: Trends Pharmacol Sci Date: 2015-03-18 Impact factor: 14.819