Interleukin-38 overexpression in keratinocytes limits desquamation but does not affect the global severity of imiquimod-induced skin inflammation in mice

SUMMARY

Psoriasis is a common chronic inflammatory skin disease that significantly impacts the patients' quality of life. Recent studies highlighted the function of the interleukin (IL)-1 family member IL-38 in skin homeostasis and suggested an anti-inflammatory role for this cytokine in psoriasis. In this study, the authors led by GCIR Professor Gaby Palmer-Lourenço, generated mice specifically overexpressing the IL-38 protein in epidermal keratinocytes. They confirmed IL-38 overexpression in the skin by Western blotting. They further detected the protein by ELISA in the plasma, as well as in conditioned media of skin explants isolated from IL-38 overexpressing mice, indicating that IL-38 produced in the epidermis is released from keratinocytes and can be found in the circulation. Unexpectedly, epidermal IL-38 overexpression did not impact the global severity of imiquimod (IMQ)-induced skin inflammation. Similarly, keratinocyte activation and differentiation in IMQ-treated skin were not affected by increased IL-38 expression and there was no global effect on local or systemic inflammatory responses. Nevertheless, the authors observed a selective inhibition of CXCL1 and IL-6 production in response to IMQ in IL-38 overexpressing skin, as well as reduced Ly6g mRNA levels, suggesting decreased neutrophil infiltration. Epidermal IL-38 overexpression also selectively affected the desquamation process during IMQ-induced psoriasis, as illustrated by reduced plaque formation. Taken together, these results validate the generation of a new mouse line allowing for tissue-specific IL-38 overexpression. Interestingly, epidermal IL-38 overexpression selectively affected specific disease-associated readouts during IMQ-induced psoriasis, suggesting a more complex role of IL-38 in the inflamed skin than previously recognized. In particular, their data highlight a potential involvement of IL-38 in the regulation of skin desquamation.

Full article: https://doi.org/10.3389/fimmu.2024.1387921

WHY IS IT IMPORTANT?

Psoriasis is a chronic inflammatory skin disease that significantly impacts patients' quality of life. In this study, GCIR researchers led by Professor Gaby Palmer-Lourenço, investigated the role of the protein interleukin-38 (IL-38) in psoriasis by generating mice with IL-38 overexpression specifically in their skin cells, known as keratinocytes. The study confirmed that IL-38 was present in the skin and circulated in the blood. Surprisingly, the overexpression of IL-38 did not affect the overall severity of psoriasis-like inflammation induced by imiquimod (IMQ). However, it selectively reduced the production of certain inflammatory markers. Importantly, IL-38 overexpression reduced plaque formation, indicating a potential role in regulating skin desquamation. These findings suggest that IL-38 might have a more complex function in skin inflammation and desquamation than previously understood.

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