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Published on: April 8, 2016
Clostridium botulinum C3bot mediated effects on cytokine-induced psoriasis-like phenotype in full-thickness skin
Astrid Rohrbeck1, Vanessa Anna Bruhn2, Nali Hussein2
1Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany. rohrbeck.astrid@mh-hannover.de.
Abstract:
Clostridium botulinum C3 exoenzyme (C3bot) exclusively inhibits RhoA, B and C by ADP-ribosylation and is therefore used as a cell-permeable tool for investigating the cellular role of these Rho-GTPases. Rho-GTPases represent a molecular switch integrating different receptor signalling to downstream cascades including transcriptional cascades that regulate various cellular processes, such as regulation of actin cytoskeleton and cell proliferation. C3bot-induced inhibition of RhoA leads to reorganization of the actin cytoskeleton, morphological changes, and inhibition of cell proliferation as well as modulation of inflammatory response. In this study, we characterized the C3bot-mediated effects on a full-thickness skin model exhibiting a psoriasis-like phenotype through the addition of cytokines. Indeed, after the addition of cytokines, a decrease in epidermal thickness, parakeratosis, and induction of IL-6 was detected. In the next step, it was studied whether C3bot caused a reduction in the cytokine-induced psoriasis-like phenotypes. Basal addition of C3bot after cytokine induction of the full-thickness skin models caused less epidermal thinning and reduced IL-6 abundance. Simultaneous basal incubation with cytokines and C3bot, IL-6 abundance was inhibited, but epidermal thickness was only moderately affected. When C3bot was added apically to the skin model, IL-6 abundance was reduced, but no further effects on the psoriasis-like phenotype of the epidermis were observed. In summary, C3bot inhibits the cytokine-induced expression of IL-6 and thus may have an impact on the pro-inflammatory immune response in the psoriasis-like phenotype.
Insights
Clostridium botulinum C3 exoenzyme (C3bot) reduces psoriasis-like skin symptoms by inhibiting RhoA GTPases. This study shows C3bot decreases IL-6 and epidermal changes in a skin model, suggesting a role in modulating inflammation.
Area of Science:
- Molecular Biology
- Dermatology
- Biochemistry
Background:
- Rho-GTPases (RhoA, B, C) are key regulators of cellular processes including actin cytoskeleton organization, proliferation, and inflammatory responses.
- Clostridium botulinum C3 exoenzyme (C3bot) is a cell-permeable inhibitor of RhoA, B, and C via ADP-ribosylation, serving as a tool to study Rho-GTPase functions.
- Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia and immune cell infiltration, often associated with elevated IL-6 levels.
Purpose of the Study:
- To investigate the effects of C3bot on a full-thickness skin model with a cytokine-induced psoriasis-like phenotype.
- To determine if C3bot can ameliorate psoriasis-like characteristics, specifically epidermal changes and IL-6 induction.
- To explore different application methods (basal vs. apical) of C3bot and their impact on the skin model.
Main Methods:
- A full-thickness skin model was established and treated with cytokines to induce a psoriasis-like phenotype, characterized by decreased epidermal thickness, parakeratosis, and increased IL-6.
- C3bot was administered to the skin models at different time points and locations (basal or apical) relative to cytokine induction.
- Changes in epidermal thickness and IL-6 abundance were quantified to assess the efficacy of C3bot treatment.
Main Results:
- Cytokine treatment led to a decrease in epidermal thickness, parakeratosis, and induced IL-6 expression, mimicking psoriasis features.
- Basal application of C3bot after cytokine induction partially reversed epidermal thinning and significantly reduced IL-6 levels.
- Simultaneous basal application of cytokines and C3bot inhibited IL-6 but only moderately affected epidermal thickness; apical C3bot application reduced IL-6 but had no significant impact on other epidermal phenotypes.
Conclusions:
- C3bot effectively inhibits cytokine-induced IL-6 expression in a psoriasis-like skin model.
- The findings suggest that C3bot has a modulatory effect on the pro-inflammatory immune response in psoriasis.
- C3bot's therapeutic potential in managing psoriasis warrants further investigation, particularly regarding its impact on Rho-GTPase-mediated inflammatory pathways.
