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Keratinocyte SR-B1 expression and targeting in cytokine-driven skin inflammation

J. Trujillo,A.E. Calvert,J.S. Rink,B. E. P. White,F. Sepulveda,D. Biyashev,Kurt Q. Lu,R. Lavker,Han Peng,Shad C. Thaxton,E. Superior,IL St Chicago

Published 2025 in Communications Medicine

ABSTRACT

Strategies to treat inflammatory skin conditions require identifying new targets involved in interactions between overlying epithelial and underlying dermal immune cells. Scavenger receptor class B type 1 (SR-B1) is a cell surface receptor that binds high-density lipoproteins (HDL) and mediates inflammatory responses in immune and endothelial cells. The SR-B1 receptor is also expressed in keratinocytes, but its role in inflammatory skin diseases remains unexplored. To investigate keratinocyte SR-B1 in the setting of inflammation, we measured its expression in skin biopsy samples obtained from patients with psoriasis; human skin explants exposed to the inflammatory cytokine, interleukin-17A (IL-17A); and mouse skin exposed to the pro-inflammatory agent, imiquimod (IMQ). We also evaluated the effects of SR-B1 knockdown on primary keratinocyte responses to IL-17A. Finally, we employed a synthetic HDL-nanoparticle (HDL NP) to investigate the therapeutic potential of targeting SR-B1 in IL-17A-stimulated keratinocytes and in male C57BL/6 mice with IMQ-induced skin inflammation. Our data show SR-B1 expression is increased in diseased human skin and in both human and mouse models of skin inflammation. SR-B1 knockdown in keratinocytes exacerbates the inflammatory response to IL-17A, whereas targeting SR-B1 with HDL NP attenuates this response. In the IMQ murine model, topical application of HDL NPs improves the skin phenotype, normalizes SR-B1 expression, and reduces molecular and cellular markers of inflammation. Overall, SR-B1 plays a role in skin inflammation and HDL NP-mediated targeting of SR-B1 in keratinocytes may offer a targeted new therapy for inflammatory skin disease. Trujillo et al. identify scavenger receptor class B type I (SR-B1) as a keratinocyte marker of skin inflammation and a potential therapeutic target. Topically delivered HDL-like nanoparticles target SR-B1, reduce inflammatory signaling in keratinocytes, and improve imiquimod-induced inflammation in murine models. Inflammatory skin diseases, like psoriasis, are common and often lack effective treatment options. A protein, called scavenger receptor class B type 1 (SR-B1), known to regulate immune responses, is present in skin cells but its role in skin inflammation has not been well studied. We show that SR-B1 expression in the skin increases in psoriasis and regulates cellular inflammatory responses. We developed a molecule that targets SR-B1 and showed that it reduces disease markers in skin cells and improves outcomes in a mouse model of psoriasis-like skin inflammation. These findings suggest that SR-B1 plays a role in skin inflammation and could be targeted with topical agents to develop new treatments for inflammatory skin disease.

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