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.

Siramesine causes preferential apoptosis of mast cells in skin biopsies from psoriatic lesions

“…So far, the principle of reducing mast‐cell populations by lysosomotropic agents has mainly been adapted to various mast‐cell types in culture and in other preclinical settings . Here, we have extended the concept into a clinically relevant context, and demonstrate that siramesine clearly reduces the number of mast cells in psoriatic skin ex vivo .…”

“…Subsequently it was shown that siramesine, in addition to its σ‐2 agonist properties, also exhibits lysosomotropic activity . In previous studies, we showed that siramesine can cause permeabilization of mast‐cell granule membranes, leading to the initiation of apoptosis . Here, we evaluated the concept of inducing mast‐cell apoptosis in a clinical setting by exploring whether siramesine can reduce mast‐cell numbers in psoriatic lesions.…”

“…A challenging prospect of these research advancements is that targeted mast‐cell apoptosis now appears to be a conceivable therapy to dampen mast‐cell‐mediated effects in various pathological conditions . In previous studies, we have highlighted the idea of using lysosomotropic agents for this purpose . Mechanistically, these agents induce permeabilization of mast‐cell granule membranes, which results in the release of granule compounds into cytosol and the subsequent triggering of reactive oxygen species and tryptase‐dependent apoptosis (Fig.…”

“…an agent that permeabilizes membranes of lysosomal organelles. Previous studies that we have carried out have shown that siramesine and other lysosomotropic agents cause secretory granule derangement in mast cells, which leads to the release of granule compounds into the cytosol, eventually triggering apoptosis . Here, we have evaluated the novel concept of targeting mast cells in a clinically relevant setting by assessing whether siramesine is able to induce apoptosis of mast cells populated in psoriatic skin.…”

Copper Regulates Maturation and Expression of an MITF:Tryptase Axis in Mast Cells

“…For immunohistochemistry, staining with was performed using a monoclonal anti-tryptase antibody, as described previously [27]. …”