Aorta in Pathologies May Function as an Immune Organ by Upregulating Secretomes for Immune and Vascular Cell Activation, Differentiation and Trans-Differentiation—Early Secretomes may Serve as Drivers for Trained Immunity

Abstract

To determine whether aorta becomes immune organ in pathologies, we performed transcriptomic analyses of six types of secretomic genes (SGs) in aorta and vascular cells and made the following findings: 1) 53.7% out of 21,306 human protein genes are classified into six secretomes, namely, canonical, caspase 1, caspase 4, exosome, Weibel–Palade body, and autophagy; 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 induced AAA, canonical, caspase 4, and exosome SGs have two expression peaks of high (day 7)-low (day 14)-high (day 28) patterns; 5) Elastase induced AAA aortas have more inflammatory/immune pathways than that of Ang-II induced 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); 8) Venous ECs from arteriovenous fistula (AVF) upregulate SGs in five secretomes; and 9) Increased some of 101 trained immunity genes and decreased trained tolerance regulator IRG1 participate in upregulations of SGs in atherosclerotic, Ang-II induced AAA and CKD aortas, and MERS-CoV infected ECs, but less in SGs upregulated in AVF ECs. IL-1 family cytokines, HIF1α, SET7 and mTOR, ROS regulators NRF2 and NOX2 partially regulate trained immunity genes; and NRF2 plays roles in downregulating SGs more than that of NOX2 in upregulating SGs. These results provide novel insights on the roles of aorta as immune organ in upregulating secretomes and driving immune and vascular cell differentiations in COVID-19, cardiovascular diseases, inflammations, transplantations, autoimmune diseases and cancers.

Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages

“…Our team previously examined the expression changes of macrophage markers, macrophage proinflammatory cytokines, and macrophage metabolism genes in 10 macrophage subsets in liver inflammatory diseases, digestive inflammatory diseases, type-1 and type-2 diabetes, metabolic syndrome, and familial hypercholesterolemia and demonstrated that liver inflammatory diseases have predominant M1 macrophage status. In addition, M1 macrophage status have a significant upregulation of proinflammatory cytokine IL-1b, which secreted during pyroptosis mechanisms (138) and also reported in our recent papers (77,139). We also found that M1 macrophages related to metabolic diseases have a significant increase in glycolysis while M2 macrophages related to TCA cycle metabolites (46).…”

“…Being an initiator caspase, activated caspase-11 functions primarily through its cleavage of key substrates. GSDMD is the primary substrate of caspase-11, and the N-terminal GSDMD cleavage fragment generated (GSDMD-NT) leads to the formation of pores (protein channels) in the plasma membrane and secretion of caspase-1 produced IL-1β and other caspase-1 dependent secretomes and caspase-11-dependent secretomes ( 139 , 146 ) into the extracellular space to promote liver inflammation (NASH), and subsequently increased hepatic pyroptosis and promotes NAFLD. Thus, caspase-11 functions as an intracellular sensor for LPS and an innate immune effector.…”

Cigarette Smoke and Morphine Promote Treg Plasticity to Th17 via Enhancing Trained Immunity

“…This phenomenon is known as trained immunity or innate immune memory [ 59 , 80 ]. Trained immunity can occur in several traditional innate immune cells such as monocytes/macrophages, natural killer (NK) cells, dendritic cells (DCs), aortic cells, innate immune functions of T cells, and Treg cells, as well as in non-traditional immune cells such as vascular smooth muscle cells (VSMCs), endothelial cells (ECs), hepatocytes, and fibroblasts [ 59 , 81 , 82 , 83 , 84 , 85 ]. Trained immunity can be induced by several pathogen-associated molecular patterns (PAMPs)/danger-associated molecular patterns (DAMPs) stimuli such as lipopolysaccharides (LPS), β-glucan, Bacillus Calmette–Guerin (BCG), oxidized low-density lipoprotein (ox-LDL), and high-fat diet [ 86 , 87 , 88 , 89 ].…”

Editorial: Insights in cardiovascular therapeutics 2022—cardiovascular innate immunity

“…Trained immunity serves as a new mechanism underlying chronic metabolic cardiovascular diseases. In addition, trained immunity can be a qualification criteria for environmental, metabolic, and infectious stimuli to become significant cardiovascular disease risk factors such as hyperlipidemia ( 22 – 27 ), hyperglycemia ( 28 – 30 ), hyperhomocysteinemia ( 31 , 32 ), cigarette smoke ( 12 , 33 , 34 ), hypertension, infections ( 11 , 35 ), metabolic syndrome, and obesity ( 23 , 36 , 37 ), which are different from in significant endogenous metabolites and compounds in the foods in inducing trained immunity and enhancing inflammation ( 8 , 33 ).…”