Trained Immunity and Reactivity of Macrophages and Endothelial Cells

Abstract

Innate immune cells can develop exacerbated immunologic response and long-term inflammatory phenotype following brief exposure to endogenous or exogenous insults, which leads to an altered response towards a second challenge after the return to a nonactivated state. This phenomenon is known as trained immunity (TI). TI is not only important for host defense and vaccine response but also for chronic inflammations such as cardiovascular and metabolic diseases such as atherosclerosis. TI can occur in innate immune cells such as monocytes/macrophages, natural killer cells, endothelial cells (ECs), and nonimmune cells, such as fibroblast. In this brief review, we analyze the significance of TI in ECs, which are also considered as innate immune cells in addition to macrophages. TI can be induced by a variety of stimuli, including lipopolysaccharides, bacillus Calmette-Guerin, and oxLDL (oxidized low-density lipoprotein), which are defined as risk factors for cardiovascular and metabolic diseases. Furthermore, TI in ECs is functional for inflammation effectiveness and transition to chronic inflammation. Rewiring of cellular metabolism of the trained cells takes place during induction of TI, including increased glycolysis, glutaminolysis, increased accumulation of tricarboxylic acid cycle metabolites and acetyl-coenzyme A production, as well as increased mevalonate synthesis. Subsequently, this leads to epigenetic remodeling, resulting in important changes in chromatin architecture that enables increased gene transcription and enhanced proinflammatory immune response. However, TI pathways and inflammatory pathways are separated to ensure memory stays when inflammation undergoes resolution. Additionally, reactive oxygen species play context-dependent roles in TI. Therefore, TI plays significant roles in EC and macrophage pathology and chronic inflammation. However, further characterization of TI in ECs and macrophages would provide novel insights into cardiovascular disease pathogenesis and new therapeutic targets.

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

“…As we and others reported, increased secretion of cytokines and chemokines are one hallmark of aortic endothelial cell activation [ 3 , 8 , 9 , 42 , 51 , 55 , 66 , 70 , 92 , 94 ]. To determine whether LPC induced nuclear localization of procaspase-1 leads to upregulation of cytokines and chemokines, we collected several sets of large secretome genes such as canonical secretome (secretory proteins with signal peptide) [ 18 ], caspase-1-Gasdermin D (GSDMD) secretome, caspase-4-GSDMD secretome, and exosome secretomes [ 20 ] as we reported [ 18 , 22 , 23 ].…”

“…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 ].…”

Organelle Crosstalk Regulators Are Regulated in Diseases, Tumors, and Regulatory T Cells: Novel Classification of Organelle Crosstalk Regulators

“…We and others recently reported that CVD stressors and risk factors such as hyperlipidemia (3,4), hyperglycemia (5), hyperhomocysteinemia (6,7), and chronic kidney disease (8)(9)(10) promote atherosclerosis and vascular inflammation via several mechanisms. These mechanisms include innate immune activation (11) of endothelial cells (ECs) (3,(12)(13)(14)(15) promoting EC injury (16); Ly6Chigh inflammatory mouse monocyte and CD40 + human monocyte differentiation (7,(17)(18)(19); disease reprogrammed macrophages (20)(21)(22); cytokine and secretome regulation (23)(24)(25)(26)(27)(28)(29)(30); decreased/transdifferentiated CD4 + Foxp3 + regulatory T cells (Treg) (24,(31)(32)(33)(34); and impaired vascular repairability of bone marrow-derived progenitor cells (35,36). In addition, we recently proposed new models such as intracellular organelle dangers (37) and reactive oxygen species (ROS) as an integrated sensing system for metabolic homeostasis and alarming (38), which indicated that metabolic reprogramming and dysfunction trigger mitochondrial (MT) ROS (4,(39)(40)(41...…”

“…These mechanisms include innate immune activation (11) of endothelial cells (ECs) (3,(12)(13)(14)(15) promoting EC injury (16); Ly6Chigh inflammatory mouse monocyte and CD40 + human monocyte differentiation (7,(17)(18)(19); disease reprogrammed macrophages (20)(21)(22); cytokine and secretome regulation (23)(24)(25)(26)(27)(28)(29)(30); decreased/transdifferentiated CD4 + Foxp3 + regulatory T cells (Treg) (24,(31)(32)(33)(34); and impaired vascular repairability of bone marrow-derived progenitor cells (35,36). In addition, we recently proposed new models such as intracellular organelle dangers (37) and reactive oxygen species (ROS) as an integrated sensing system for metabolic homeostasis and alarming (38), which indicated that metabolic reprogramming and dysfunction trigger mitochondrial (MT) ROS (4,(39)(40)(41)(42); caspase-1/inflammasome activation (8, 10) downregulated histone modification enzymes (43) and increased expressions of trained immunity pathway enzymes (22,39,(44)(45)(46)…”

The iterative lipid impact on inflammation in atherosclerosis

“…In atherosclerosis, this phenomenon has been observed for both mmLDL and Lp(a) on a cellular level [ 62 , 72 , 73 ]. Brief exposure of isolated human monocytes to mmLDL induced prolonged expression of pro-inflammatory proteins including IL-6, IL-18 and MCP-1 [ 72 ].…”