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

Abstract

To examine whether the expressions of 260 organelle crosstalk regulators (OCRGs) in 16 functional groups are modulated in 23 diseases and 28 tumors, we performed extensive -omics data mining analyses and made a set of significant findings: (1) the ratios of upregulated vs. downregulated OCRGs are 1:2.8 in acute inflammations, 1:1 in metabolic diseases, 1:1.2 in autoimmune diseases, and 1:3.8 in organ failures; (2) sepsis and trauma-upregulated OCRG groups such as vesicle, mitochondrial (MT) fission, and mitophagy but not others, are termed as the cell crisis-handling OCRGs. Similarly, sepsis and trauma plus organ failures upregulated seven OCRG groups including vesicle, MT fission, mitophagy, sarcoplasmic reticulum–MT, MT fusion, autophagosome–lysosome fusion, and autophagosome/endosome–lysosome fusion, classified as the cell failure-handling OCRGs; (3) suppression of autophagosome–lysosome fusion in endothelial and epithelial cells is required for viral replications, which classify this decreased group as the viral replication-suppressed OCRGs; (4) pro-atherogenic damage-associated molecular patterns (DAMPs) such as oxidized low-density lipoprotein (oxLDL), lipopolysaccharide (LPS), oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (oxPAPC), and interferons (IFNs) totally upregulated 33 OCRGs in endothelial cells (ECs) including vesicle, MT fission, mitophagy, MT fusion, endoplasmic reticulum (ER)–MT contact, ER– plasma membrane (PM) junction, autophagosome/endosome–lysosome fusion, sarcoplasmic reticulum–MT, autophagosome–endosome/lysosome fusion, and ER–Golgi complex (GC) interaction as the 10 EC-activation/inflammation-promoting OCRG groups; (5) the expression of OCRGs is upregulated more than downregulated in regulatory T cells (Tregs) from the lymph nodes, spleen, peripheral blood, intestine, and brown adipose tissue in comparison with that of CD4+CD25− T effector controls; (6) toll-like receptors (TLRs), reactive oxygen species (ROS) regulator nuclear factor erythroid 2-related factor 2 (Nrf2), and inflammasome-activated regulator caspase-1 regulated the expressions of OCRGs in diseases, virus-infected cells, and pro-atherogenic DAMP-treated ECs; (7) OCRG expressions are significantly modulated in all the 28 cancer datasets, and the upregulated OCRGs are correlated with tumor immune infiltrates in some tumors; (8) tumor promoter factor IKK2 and tumor suppressor Tp53 significantly modulate the expressions of OCRGs. Our findings provide novel insights on the roles of upregulated OCRGs in the pathogenesis of inflammatory diseases and cancers, and novel pathways for the future therapeutic interventions for inflammations, sepsis, trauma, organ failures, autoimmune diseases, metabolic cardiovascular diseases (CVDs), and cancers.

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

“…Taken together, our results have demonstrated that first , 53.7% out of 21,306 human protein-encoding genes in the six secretomes carry out secretory functions physiologically and pathophysiologically; second , out of six types of secretomes, canonical, caspase 1, caspase 4 and exosome secretomes are the large secretomes with more than 900 proteins; and third , although different types of secretomes share some functions such as regulated exocytosis, regulation of cell adhesion, innate and adaptive immune systems, positive regulation of organelle organization ( 64 ), and others, except autophagy secretome, five types of secretomes have specific functional pathways.…”

Editorial: Endothelial cells as innate immune cells

“…However, immunological characters of endothelial cells have been poorly characterized due to the fact that endothelial cells have not been recognized as innate immune cells in the field. To fill in this significant knowledge gap, ten years ago based on more than ten major innate immune functional aspects that are shared by the prototypic innate immune cell type -macrophages and endothelial cells, we proposed a new concept that endothelial cells are innate immune cells (2,4), which was further supported by our experimental data (5)(6)(7)(8)(9)(10)(11)(12)(13) analyses (Shao et al,15). The Molecular Innate Immunity field is continuously evolving, and we greatly appreciate the Molecular Innate Immunity section editors gave us this opportunity to organize this Research Topic and work with other investigators to explore this important topic further.…”

“…However, immunological characters of endothelial cells have been poorly characterized due to the fact that endothelial cells have not been recognized as innate immune cells in the field. To fill in this significant knowledge gap, ten years ago based on more than ten major innate immune functional aspects that are shared by the prototypic innate immune cell type - macrophages and endothelial cells, we proposed a new concept that endothelial cells are innate immune cells ( 2 , 4 ), which was further supported by our experimental data ( 5 – 13 ) analyses ( Shao et al. , 15 ).…”

Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation

“…One limitation of all the RNA-Seq data analyses is that due to the low-throughput nature of verification techniques in every laboratory, including ours, we could not verify every result we found with the analyses of high-throughput data, which are similar to all the studies with RNA-Seq ( 19 , 59 ), single-cell RNA-Seq, metabolomics ( 23 ), chromatin immunoprecipitation (CHIP)-Seq ( 24 , 44 ), and other-omics data ( 11 , 138 , 139 ). We acknowledge that carefully designed in vitro and in vivo experimental models will be needed in the future to verify the LPI-upregulated genes further and the underlying mechanisms we report here ( 9 , 140 ).…”