The Role of Adenylyl Cyclase-Associated Protein1 (CAP1) in Transendothelial Migration of Monocytes to Promote Chronic Inflammation

Abstract

Background Resistin, originally described as an adipocyte-specific hormone, was first discovered in obese mice and named for its ability to resist insulin action. Resistin has been proposed to be an important mediator between obesity and diabetes. Although it is mainly secreted from adipocytes in rodents, interestingly, significant levels of resistin expression in humans are mainly found in mononuclear leukocytes, macrophages and bone marrow cells. Recently, various studies indicate that resistin plays important regulatory roles in a variety of human diseases, such as altered glucose homeostasis, atherosclerosis, cardiovascular disease, non-alcoholic fatty liver disease and chronic low-grade inflammation. Even though there is growing evidence that links resistin-mediated chronic inflammation, the connection between the inflammatory function of human resistin and its role in metabolic disease has not been clarified yet, due to lack of information about its corresponding receptor and signaling mechanism. Recently, our group identified adenylyl cyclase-associated protein 1 (CAP1), as a novel functional receptor for human resistin, and clarified its intracellular signaling pathway to modulate inflammation of human monocytes. In the present study, I investigated the physiological role of CAP1, as a functional receptor of human resistin in endothelial cells with the mechanism being distinguished from monocytes. I found that resistin bound to CAP1, activated adenylyl cyclase, and increased cell adhesion molecules such as hICAM-1 and hVCAM-1 through the cAMP-PKA-NF-κB signaling pathway in endothelial cells. As a result, Resistin promoted the transendothelial migration (TEM) of monocytes. Methods To examine whether CAP1 is a functional receptor of human resistin in endothelial cells in vitro, I cloned adenovirus expressing human CAP1. Also, knockdown of CAP1 was achieved by using siRNA. For in vivo loss of function studies, I generated the CAP1 heterozygous deficient mice (CAP1+-) using gene editing system TALENs (TAL effector nuclease). Results In the present study, I newly identified that CAP1 serves as a functional receptor of human resistin and plays a role as a critical regulator of inflammation in endothelial cells. Resistin binding to CAP1 dissociates CAP1-AC3-CAV1 complex, results in activation of adenylyl cyclase, and stimulates cAMP-PKA-NF-κB pathway followed by overexpression of ICAM-1 and VCAM-1 expression. Finally, these results facilitate the transendothelial migration (TEM) of monocytes. Conclusions CAP1 of endothelial cells is an important regulator of the infiltration of mononuclear cells into inflamed tissues as a functional receptor for human resistin.