STRA6-RBP4 AXIS IN ACUTE LUNG INJURY

Retinoids are a critical component of lung development, health, function, and immunity. It is known that retinoid deficiency contributes to a lack of immunocompetency and worsened rates of inflammatory lung infections. Previous work has demonstrated an uncharacterized relationship between retinoid supplementation and inflammatory lung disease, with clinical investigations indicating that excessive supplementation may have no effect or even worsen respiratory infections. Despite this, the pathway of retinoid delivery to the lung remains poorly understood. The general assumption, without empirical evidence, is that the STRA6-RBP4 axis is the mechanism of ROH delivery to the lung. In this work, we demonstrated empirically that during acute lung injury (ALI), the Retinol Binding Protein 4 (RBP4) – Cell Surface Signaling Receptor and Transporter of Retinol (STRA6) axis, referred to as the RBP4-STRA6 axis, does not contribute to lung retinoid accumulation. We also show that STRA6 is upregulated in lung macrophages during ALI. Furthermore, our data provide experimental evidence that the RBP4-STRA6 axis contributes to the severity of the acute inflammatory response and, therefore, the severity of ALI. Our data suggest Stra6 as a candidate for cell-specific pharmacological interventions to treat ALI, as well as indicate that to approach retinoid supplementation to the lung from a therapeutic lens, a detailed understanding of the physiological mechanisms of retinoid delivery, and their contribution to specific cell actions in a population as diverse as the lung must be comprehensively understood to avoid negative outcomes or toxicities from treatment.