title: Ablation of human skin mast cells in situ by lysosomotropic agents.
abstract: Mast cells are known to have a detrimental impact on numerous types of inflammatory skin diseases such as contact dermatitis, atopic eczema and cutaneous mastocytosis. Regimens that dampen skin mast cell-mediated activities can thus offer an attractive therapeutic option under such circumstances. As mast cells are known to secrete a large array of potentially pathogenic compounds, both from preformed stores in secretory lysosomes (granules) and after de novo synthesis, mere inhibition of degranulation or interference with individual mast cell mediators may not be sufficient to provide an effective blockade of harmful mast cell activities. An alternative strategy may therefore be to locally reduce skin mast cell numbers. Here, we explored the possibility of using lysosomotropic agents for this purpose, appreciating the fact that mast cell granules contain bioactive compounds prone to trigger apoptosis if released into the cytosolic compartment. Based on this principle, we show that incubation of human skin punch biopsies with the lysosomotropic agents siramesine or Leu-Leu methyl ester preferably ablated the mast cell population, without causing any gross adverse effects on the skin morphology. Subsequent analysis revealed that mast cells treated with lysosomotropic agents predominantly underwent apoptotic rather than necrotic cell death. In summary, this study raises the possibility of using lysosomotropic agents as a novel approach to targeting deleterious mast cell populations in cutaneous mastocytosis and other skin disorders negatively influenced by mast cells.
authors: Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden.
authors: Eva
authors: E
authors: Hagforsen
authors: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors: Aida
authors: A
authors: Paivandy
authors: Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
authors: Maria
authors: M
authors: Lampinen
authors: Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden.
authors: Simone
authors: S
authors: Weström
authors: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors: Gabriela
authors: G
authors: Calounova
authors: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors: Fabio R
authors: FR
authors: Melo
authors: Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden.
authors: Ola
authors: O
authors: Rollman
authors: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.|Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors: Gunnar
authors: G
authors: Pejler
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D034701:Mastocytosis, Cutaneous / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D013141:Spiro Compounds / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D007166:Immunosuppressive Agents; D007211:Indoles; C109644:Lu 28-179; D013141:Spiro Compounds; C045139:leucyl-leucine-methyl ester
keywords: LLME; apoptosis; lysosomotropic agents; mast cells; siramesine