Canonical Secretomes, Innate Immune Caspase-1-, 4/11-Gasdermin D Non-Canonical Secretomes and Exosomes May Contribute to Maintain Treg-Ness for Treg Immunosuppression, Tissue Repair and Modulate Anti-Tumor Immunity via ROS Pathways
Drummer IV, Charles
Luo, Jin J.
Choi, Eric T.
GroupCenters for Cardiovascular Research (Temple University)
Metabolic Disease Research & Thrombosis Research (Temple University)
Inflammation, Translational & Clinical Lung Research (Temple University)
SubjectCD4+Foxp3+ regulatory T cells (Treg)
Innate immune caspase-1 dependent secretome
Innate immune caspase-4/11 dependent secretome
Immune checkpoint receptors
Permanent link to this recordhttp://hdl.handle.net/20.500.12613/7015
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AbstractWe performed a transcriptomic analyses using the strategies we pioneered and made the following findings: 1) Normal lymphoid Tregs, diseased kidney Tregs, splenic Tregs from mice with injured muscle have 3, 17 and 3 specific (S-) pathways, respectively; 2) Tumor splenic Tregs share 12 pathways with tumor Tregs; tumor splenic Tregs and tumor Tregs have 11 and 8 S-pathways, respectively; 3) Normal and non-tumor disease Tregs upregulate some of novel 2641 canonical secretomic genes (SGs) with 24 pathways, and tumor Tregs upregulate canonical secretomes with 17 pathways; 4) Normal and non-tumor disease tissue Tregs upregulate some of novel 6560 exosome SGs with 56 exosome SG pathways (ESP), tumor Treg ESP are more focused than other Tregs; 5) Normal, non-tumor diseased Treg and tumor Tregs upregulate some of novel 961 innate immune caspase-1 SGs and 1223 innate immune caspase-4 SGs to fulfill their tissue/SG-specific and shared functions; 6) Most tissue Treg transcriptomes are controlled by Foxp3; and Tumor Tregs had increased Foxp3 non-collaboration genes with ROS and 17 other pathways; 7) Immune checkpoint receptor PD-1 does, but CTLA-4 does not, play significant roles in promoting Treg upregulated genes in normal and non-tumor disease tissue Tregs; and tumor splenic and tumor Tregs have certain CTLA-4-, and PD-1-, non-collaboration transcriptomic changes with innate immune dominant pathways; 8) Tumor Tregs downregulate more immunometabolic and innate immune memory (trained immunity) genes than Tregs from other groups; and 11) ROS significantly regulate Treg transcriptomes; and ROS-suppressed genes are downregulated more in tumor Tregs than Tregs from other groups. Our results have provided novel insights on the roles of Tregs in normal, injuries, regeneration, tumor conditions and some of canonical and innate immune non-canonical secretomes via ROS-regulatory mechanisms and new therapeutic targets for immunosuppression, tissue repair, cardiovascular diseases, chronic kidney disease, autoimmune diseases, transplantation, and cancers.
CitationNi D, Tang T, Lu Y, Xu K, Shao Y, Saaoud F, Saredy J, Liu L, Drummer C IV, Sun Y, Hu W, Lopez-Pastrana J, Luo JJ, Jiang X, Choi ET, Wang H and Yang X (2021) Canonical Secretomes, Innate Immune Caspase-1-, 4/11-Gasdermin D Non-Canonical Secretomes and Exosomes May Contribute to Maintain Treg-Ness for Treg Immunosuppression, Tissue Repair and Modulate Anti-Tumor Immunity via ROS Pathways. Front. Immunol. 12:678201. doi: 10.3389/fimmu.2021.678201
Citation to related workFrontiers Media
Has partFrontiers in Immunology, Vol. 12
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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 ImmunityCardiovascular Research Center (Temple University); Center for Metabolic Disease Research (Temple University); Sol Sherry Thrombosis Research (Temple University) (2022-03-07)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.
Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell ActivationCenter for Cardiovascular Research (Temple University); Center for Microbiology and Immunology (Temple University); Alzheimer's Center (Temple University); Center for Inflammation and Lung Research (Temple University) (2021-11-29)To determine whether pro-inflammatory lipid lysophosphatidylinositols (LPIs) upregulate the expressions of membrane proteins for adhesion/signaling and secretory proteins in human aortic endothelial cell (HAEC) activation, we developed an EC biology knowledge-based transcriptomic formula to profile RNA-Seq data panoramically. We made the following primary findings: first, G protein-coupled receptor 55 (GPR55), the LPI receptor, is expressed in the endothelium of both human and mouse aortas, and is significantly upregulated in hyperlipidemia; second, LPIs upregulate 43 clusters of differentiation (CD) in HAECs, promoting EC activation, innate immune trans-differentiation, and immune/inflammatory responses; 72.1% of LPI-upregulated CDs are not induced in influenza virus-, MERS-CoV virus- and herpes virus-infected human endothelial cells, which hinted the specificity of LPIs in HAEC activation; third, LPIs upregulate six types of 640 secretomic genes (SGs), namely, 216 canonical SGs, 60 caspase-1-gasdermin D (GSDMD) SGs, 117 caspase-4/11-GSDMD SGs, 40 exosome SGs, 179 Human Protein Atlas (HPA)-cytokines, and 28 HPA-chemokines, which make HAECs a large secretory organ for inflammation/immune responses and other functions; fourth, LPIs activate transcriptomic remodeling by upregulating 172 transcription factors (TFs), namely, pro-inflammatory factors NR4A3, FOS, KLF3, and HIF1A; fifth, LPIs upregulate 152 nuclear DNA-encoded mitochondrial (mitoCarta) genes, which alter mitochondrial mechanisms and functions, such as mitochondrial organization, respiration, translation, and transport; sixth, LPIs activate reactive oxygen species (ROS) mechanism by upregulating 18 ROS regulators; finally, utilizing the Cytoscape software, we found that three mechanisms, namely, LPI-upregulated TFs, mitoCarta genes, and ROS regulators, are integrated to promote HAEC activation. Our results provide novel insights into aortic EC activation, formulate an EC biology knowledge-based transcriptomic profile strategy, and identify new targets for the development of therapeutics for cardiovascular diseases, inflammatory conditions, immune diseases, organ transplantation, aging, and cancers.
Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammationCenter of Cardiovascular Research (Temple University); Center of Inflammation and Lung Research (Temple University) (2021-09-28)To determine the roles of nuclear localization of pro-caspase-1 in human aortic endothelial cells (HAECs) activated by proatherogenic lipid lysophosphatidylcholine (LPC), we examined cytosolic and nuclear localization of pro-caspase-1, identified nuclear export signal (NES) in pro-caspase-1 and sequenced RNAs. We made the following findings: 1) LPC increases nuclear localization of procaspase-1 in HAECs. 2) Nuclear pro-caspase-1 exports back to the cytosol, which is facilitated by a leptomycin B-inhibited mechanism. 3) Increased nuclear localization of pro-caspase-1 by a new NES peptide inhibitor upregulates inflammatory genes in oxidative stress and Th17 pathways; and SUMO activator N106 enhances nuclear localization of pro-caspase-1 and caspase-1 activation (p20) in the nucleus. 4) LPC plus caspase-1 enzymatic inhibitor upregulates inflammatory genes with hypercytokinemia/hyperchemokinemia and interferon pathways, suggesting a novel capsase-1 enzyme-independent inflammatory mechanism. 5) LPC in combination with NES inhibitor and caspase-1 inhibitor upregulate inflammatory gene expression that regulate Th17 activation, endotheli-1 signaling, p38-, and ERK- MAPK pathways. To examine two hallmarks of endothelial activation such as secretomes and membrane protein signaling, LPC plus NES inhibitor upregulate 57 canonical secretomic genes and 76 exosome secretomic genes, respectively, promoting four pathways including Th17, IL-17 promoted cytokines, interferon signaling and cholesterol biosynthesis. LPC with NES inhibitor also promote inflammation via upregulating ROS promoter CYP1B1 and 11 clusters of differentiation (CD) membrane protein pathways. Mechanistically, all the LPC plus NES inhibitor-induced genes are significantly downregulated in CYP1B1-deficient microarray, suggesting that nuclear caspase-1-induced CYP1B1 promotes strong inflammation. These transcriptomic results provide novel insights on the roles of nuclear caspase-1 in sensing DAMPs, inducing ROS promoter CYP1B1 and in regulating a large number of genes that mediate HAEC activation and inflammation. These findings will lead to future development of novel therapeutics for cardiovascular diseases (CVD), inflammations, infections, transplantation, autoimmune disease and cancers. (total words: 284).