Endothelial Immunity Trained by Coronavirus Infections, DAMP Stimulations and Regulated by Anti-Oxidant NRF2 May Contribute to Inflammations, Myelopoiesis, COVID-19 Cytokine Storms and Thromboembolism

Abstract

To characterize transcriptomic changes in endothelial cells (ECs) infected by coronaviruses, and stimulated by DAMPs, the expressions of 1311 innate immune regulatomic genes (IGs) were examined in 28 EC microarray datasets with 7 monocyte datasets as controls. We made the following findings: The majority of IGs are upregulated in the first 12 hours post-infection (PI), and maintained until 48 hours PI in human microvascular EC infected by middle east respiratory syndrome-coronavirus (MERS-CoV) (an EC model for COVID-19). The expressions of IGs are modulated in 21 human EC transcriptomic datasets by various PAMPs/DAMPs, including LPS, LPC, shear stress, hyperlipidemia and oxLDL. Upregulation of many IGs such as nucleic acid sensors are shared between ECs infected by MERS-CoV and those stimulated by PAMPs and DAMPs. Human heart EC and mouse aortic EC express all four types of coronavirus receptors such as ANPEP, CEACAM1, ACE2, DPP4 and virus entry facilitator TMPRSS2 (heart EC); most of coronavirus replication-transcription protein complexes are expressed in HMEC, which contribute to viremia, thromboembolism, and cardiovascular comorbidities of COVID-19. ECs have novel trained immunity (TI), in which subsequent inflammation is enhanced. Upregulated proinflammatory cytokines such as TNFα, IL6, CSF1 and CSF3 and TI marker IL-32 as well as TI metabolic enzymes and epigenetic enzymes indicate TI function in HMEC infected by MERS-CoV, which may drive cytokine storms. Upregulated CSF1 and CSF3 demonstrate a novel function of ECs in promoting myelopoiesis. Mechanistically, the ER stress and ROS, together with decreased mitochondrial OXPHOS complexes, facilitate a proinflammatory response and TI. Additionally, an increase of the regulators of mitotic catastrophe cell death, apoptosis, ferroptosis, inflammasomes-driven pyroptosis in ECs infected with MERS-CoV and the upregulation of pro-thrombogenic factors increase thromboembolism potential. Finally, NRF2-suppressed ROS regulate innate immune responses, TI, thrombosis, EC inflammation and death. These transcriptomic results provide novel insights on the roles of ECs in coronavirus infections such as COVID-19, cardiovascular diseases (CVD), inflammation, transplantation, autoimmune disease and cancers.

Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation

“…IL-21 receptor (IL21R) promotes inflammation in myocardial infarction [ 108 ] and respiratory disease [ 109 ]. CEACAM1 is a coronavirus receptor on endothelial cells as we reported [ 54 ] and promotes vascular aging process [ 110 ]. L1CAM regulates microRNAs associated with inflammation and progression of Alzheimer's disease and Parkinson's disease [ 111 ].…”

“…Our and others’ previous reports showed that human aortic endothelial cells (EC) are innate immune cells that have inflammasome/caspase-1 functions in sensing PAMPs and DAMPs [ 3 , 9 , 51 , 54 , 55 , 120 ]. However, several important questions remained: i) whether procaspase-1 or activated caspase-1 are localized in the nucleus in sensing nuclear DAMPs in HAECs during pyroptosis; ii) what the transcriptomic regulation functions of procaspase-1 in modulating inflammation if localized in the nucleus; iii) whether procaspase-1 has nuclear export signal; iv) whether procaspase-1 is activated in the nucleus after sensing conditional DAMPs; and v) whether procaspase-1 and/or activated caspase-1 have enzymatic activity-independent functions in the nucleus of HAECs.…”

“…Due to its vast coverage and the nature of being the first cell type to encounter any PAMPs/DAMPs in the blood circulation, the endothelium (endothelial cells, EC) [ 46 ] could function as the primary intravascular sentinel system [ [47] , [48] , [49] ]. Thus, we compared EC to prototypic innate immune cells such as macrophages [ 50 ] in 13 innate immune features, and proposed a new paradigm that EC are innate immune cells [ 2 , 3 , 51 ], which was further supported by our new paper examining the expression changes of 1311 innate immune regulatomic genes (IGs) [ 52 , 53 ] in ECs and reviews [ 54 , 55 ]. We introduced new concepts that mitochondrial reactive oxygen species (mtROS) and proton leak mediate physiological activation and pathological activation of EC [ [56] , [57] , [58] , [59] ]; ROS systems are a new integrated network for sensing homeostasis and alarming stresses [ 60 ].…”

“…We introduced new concepts that mitochondrial reactive oxygen species (mtROS) and proton leak mediate physiological activation and pathological activation of EC [ [56] , [57] , [58] , [59] ]; ROS systems are a new integrated network for sensing homeostasis and alarming stresses [ 60 ]. Moreover, under the stimulation by hyperlipidemia, EC have a novel prolonged activation status, with four innate immune features including upregulation of EC adhesion molecules [ 61 ] and secretion of cytokines and chemokines (secretomes) [ 22 , 23 , 54 , 62 ], upregulation of additional DAMP receptors, and increased expression of co-signaling receptors and MHC class II molecules [ 43 ]. However, it remains unknown that whether proatherogenic DAMPs-induced procaspase-1 nuclear localization modulates aortic endothelial cell secretomes, membrane protein signaling and ROS regulators [ 60 , 63 ] in aortic endothelial cells.…”

The Immunological Factors Predisposing to Severe Covid-19 Are Already Present in Healthy Elderly and Men

“…Trained immunity can be beneficial for the host in terms of protection against heterologous infection, but dysregulated trained immunity response could result in pathological conditions as it was described in autoinflammatory diseases ( 48 , 49 ). A recent study has described induction of trained immunity by SARS-CoV-2 infection ( 50 ), and it has been proposed that this contributes to the acute dysregulation during the disease both an endothelial and immune cell level ( 51 ).…”