Neutrophil-Specific Syk Expression Is Crucial for Skin Disease in Experimental Epidermolysis Bullosa Acquisita

by Selleckchem | Nov 29 2023

Autoantibodies against the dermal-epidermal junction component type VII collagen (C7) trigger skin disease in the inflammatory form of epidermolysis bullosa acquisita. We have previously identified the Syk tyrosine kinase as a crucial participant in anti-C7 antibody-induced experimental epidermolysis bullosa acquisita. However, it is still unclear which cellular lineage needs to express Syk during the disease process. In this study, we show that the loss of Syk, specifically from neutrophils, results in complete protection from the anti-C7 antibody-initiated skin disease both macroscopically and microscopically. Mice with a neutrophil-specific Syk deletion had decreased neutrophil accumulation and abrogated CXCL2 and IL-1β levels in the skin upon anti-C7 treatment, whereas isolated Syk-deficient neutrophils had decreased superoxide release, cell spreading, and cytokine release on C7-anti-C7 immune complex surfaces. Entospletinib and lanraplenib, two second-generation Syk-specific inhibitors, effectively abrogated immune complex-induced responses of human neutrophils and decreased the anti-C7 antibody-initiated, neutrophil-mediated ex vivo dermal-epidermal separation in human skin samples. Taken together, these results point to a crucial role for Syk in neutrophils in the development and progression of epidermolysis bullosa acquisita and suggest Syk inhibition as a potential therapeutic strategy.

Comments:

The passage you provided discusses a research study on epidermolysis bullosa acquisita (EBA), a skin disease caused by autoantibodies targeting type VII collagen (C7) in the dermal-epidermal junction. The study aimed to understand the role of Syk tyrosine kinase in the disease process and determine the specific cellular lineage expressing Syk during EBA. Here are the key findings from the study:

1. **Autoantibodies and Disease Triggering:** Autoantibodies against C7 initiate skin disease in EBA.

2. **Role of Syk Tyrosine Kinase:** Syk tyrosine kinase was identified as a crucial participant in anti-C7 antibody-induced EBA.

3. **Specificity to Neutrophils:** The study found that the loss of Syk, specifically from neutrophils, provided complete protection from the skin disease caused by anti-C7 antibodies. Mice with a neutrophil-specific Syk deletion showed no signs of the disease both macroscopically and microscopically.

4. **Mechanisms of Protection:** Neutrophil-specific Syk deletion resulted in decreased neutrophil accumulation in the skin and reduced levels of CXCL2 and IL-1β, indicating a decreased inflammatory response. Syk-deficient neutrophils exhibited impaired functions, such as decreased superoxide release, cell spreading, and cytokine release, specifically in response to C7-anti-C7 immune complexes.

5. **Therapeutic Implications:** Second-generation Syk-specific inhibitors, Entospletinib and Lanraplenib, were effective in inhibiting immune complex-induced responses of human neutrophils. These inhibitors also decreased neutrophil-mediated ex vivo dermal-epidermal separation in human skin samples, indicating their potential as therapeutic agents for EBA.

In summary, the study demonstrates that Syk inhibition, especially in neutrophils, plays a crucial role in the development and progression of epidermolysis bullosa acquisita. Targeting Syk with specific inhibitors like Entospletinib and Lanraplenib could be a promising therapeutic strategy for treating this skin disease.