Aorta In Pathologies May Function As An Immune Organ By Upregulating Secretomes For Immune Cell Activation, Differentiation And Trans-differentiation

Introduction: Six types of secertomes have been identified in past years. Single cell RNA-seq studies identified many new vascular and immune cell subsets in various aortic disease. However, the roles of new secretomes in aortic vascular cells remains unknown. Similar to traditional immune organs such as lymph nodes where native cells are polarized, transdifferentiated, matured. We hypothesis aorta serves as an immune organ by using secretomes in pathological condition. Methods: We performed transcriptomic analyses of six types of secretomic genes (SGs) including canonical secretome, caspase-1-Gasdermin D secretome, caspase-4-Gasdermin D secretome, exosome secretomes, Weibel-Palade bodies, and autophagy secretome in aorta and vascular cells and made the following findings: 1) 53.7% out of 21,306 human protein genes are in the six secretomes; 2) Atherosclerosis (AS), chronic kidney disease (CKD) and abdominal aortic aneurysm (AAA) modulate six secretomes in aortas; and Middle East Respiratory Syndrome Coronavirus (MERS-CoV, COVID-19 homologous) infected endothelial cells (ECs) and angiotensin II (Ang II) treated vascular smooth muscle cells (VSMCs) modulate six secretomes; 3) AS aortas upregulate T and B cell immune SGs; CKD aortas upregulate SGs for cardiac hypertrophy, and hepatic fibrosis; and AAA aorta upregulate SGs for neuromuscular signaling and protein catabolism; 4) Ang II-AAA, canonical, caspase-4, and exosome SGs all have two expression peaks of high (Day 7, D7)-low (D14)-high (D28) patterns; 5) Elastase AAA aortas have more inflammatory/immune pathways than that of Ang II AAA aortas; 6) Most disease-upregulated cytokines in aorta may be secreted via canonical and exosome secretomes; 7) Canonical and caspase-1 SGs play roles at early MERS-CoV infected ECs whereas caspase-4 and exosome SGs play roles in late/chronic phases; and the early upregulated canonical and caspase-1 SGs may function as drivers for trained immunity (innate immune memory). These results provide novel insights on the roles of aorta as immune organ in upregulating secretomes and driving immune cell differentiations in COVID-19, cardiovascular diseases, inflammations, transplantations, autoimmune diseases and cancers.