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

Introduction

Epithelial and surveilling innate immune cells are the first line of defense against chemical, mechanical, microbial, and other insults at biological barriers^{1, 2–3}. Pathologic changes resulting from acute and chronic inflammation can affect barrier organs and tissues including the skin (e.g., psoriasis and atopic dermatitis), vasculature (e.g., atherosclerosis), lung (e.g., asthma) and intestine (e.g., inflammatory bowel disease)^{4, 5–6}. In many cases, a re-enforcing cycle of communication between epithelial cells and immune cells perpetuates disease resulting in progression and relapse. Local and infiltrating immune cells produce inflammatory mediators that activate epithelial cells and alter differentiation leading to cell proliferation and tissue damage^{7, 8–9}. Epithelial cells also drive pathogenic processes by secreting chemokines, cytokines, and reactive oxygen species (ROS) that amplify inflammatory signaling and immune cell recruitment^5,8,9. As such, understanding new mechanisms of targeting epithelial cells to inhibit inflammatory cycles that perpetuate disease is a promising opportunity for developing novel therapeutics that can be topically delivered.

Targeting epithelial cells requires identification of molecules that participate in the maintenance of epithelial cell integrity and that become dysregulated in disease. The lipoprotein receptor, scavenger receptor class B type 1 (SR-B1), is expressed in epithelial tissues^{10, 11, 12–13} and is a known therapeutic target for modulating immune and vascular endothelial cells in the context of immunometabolic disease (e.g., atherosclerosis)^{14, 15–16}. Moreover, SR-B1 is upregulated in numerous malignancies where it supports cell survival and proliferation under metabolic and redox stress¹⁷. In the skin, the SR-B1 receptor has been shown to directly contribute to epithelial cell differentiation and wound repair^13,18,19. Interestingly, cigarette smoke was found to induce time-dependent changes in SR-B1 expression and localization in keratinocytes²⁰, which potentially reflects its dynamic role in skin injury response mechanisms. Therefore, better understanding the role of SR-B1 in epithelial inflammatory responses could uncover mechanistic insights in the study of inflammatory diseases affecting barrier organs. Further, it provides the opportunity for SR-B1 ligands to be used as novel diagnostics and targeted therapeutics.

High-density lipoprotein (HDL) endowed with the defining protein, apolipoprotein A-I (apo A-I), is the high-affinity ligand of SR-B1¹⁶. Native HDL binding to SR-B1 can result in the exchange of HDL-associated lipids (e.g., phospholipids, cholesterol,...