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
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Has partFrontiers in Immunology, Vol. 12
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The Role of the Innate Immune System in Programmed Cell DeathBalachandran, Siddharth; Brodsky, Igor; Monestier, Marc; Rall, Glenn F.; Tükel, Çagla; Zaidi, M. Raza (Temple University. Libraries, 2018)Infectious diseases are the leading cause of illness worldwide, leading to over 20 million hospitalizations each year in the United States alone. Although numerous diseases are treatable with vaccines and pharmacological agents, including antibiotics, a large fraction of infections remain poorly controlled, mainly due to lack of effective therapies and/or vaccines. Two such infectious agents are influenza A virus and the bacterium Salmonella enterica. Influenza A virus is transmitted through the aerosol route and infects lung epithelial cells, while Salmonella is transmitted via the fecal-oral route and infects the cells lining the intestine of the host. In each case, the first lines of defense against these infectious agents are non-phagocytic cells. How these pathogens are controlled in non-phagocytic cells dictates the overall outcome of infection; however there are significant gaps in our knowledge of how non-phagocytic cells respond to influenza A virus and Salmonella. Therefore, studying the fate of these cells during the course of infection is of crucial importance to disease outcome. In each case, the regulated (or programmed) death of the infected cell may represent an important pathogen clearance mechanism. Programmed cell death can be non-inflammatory (e.g., apoptosis) or pro-inflammatory (e.g., necroptosis and pyroptosis). In this dissertation, I outline experiments carried out to identify the pathways of programmed cell death activated by Salmonella and influenza A virus in their respective target non-phagocytic cells, both in vitro and in vivo. My work outlines new pathways of cell death activated by these pathogens and new mechanisms of both viral and bacterial clearance. This will have broad implications in the clearance of pathogens, and new therapeutic avenues to pursue upon treating infections.
HLA Expression Correlates to the Risk of Immune Checkpoint Inhibitor-Induced PneumonitisCenter for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine (Temple University) (2020-08-25)Tumor-infiltrating T cell rescue by programmed cell death receptor-1 (PD-1)/PD-1 ligand-1 (PD-L1) immune checkpoint blockade is a recommended treatment for malignant diseases, including metastatic non-small-cell lung cancer (mNSCLC), malignant melanoma (MM), head and neck, kidney, and urothelial cancer. Monoclonal antibodies (mAbs) against either PD-1 or PD-L1 are active agents for these patients; however, their use may be complicated by unpredictable immune-related adverse events (irAEs), including immune-related pneumonitis (IRP). We carried out a retrospective multi-institutional statistical analysis to investigate clinical and biological parameters correlated with IRP rate on a cohort of 256 patients who received real-world treatment with PD-1/PD-L1 blocking mAbs. An independent radiological review board detected IRP in 29 patients. We did not find statistical IRP rate correlation with gender, tumor type, specific PD-1 or PD-L1 blocking mAbs, radiation therapy, inflammatory profile, or different irAEs. A higher IRP risk was detected only in mNSCLC patients who received metronomic chemotherapy +/− bevacizumab compared with other treatments prior PD-1/PD-L1 blockade. Moreover, we detected a strong correlation among the IRP rate and germinal expression of HLA-B*35 and DRB1*11, alleles associated to autoimmune diseases. Our findings may have relevant implications in predicting the IRP rate in mNSCLC patients receiving PD-1/PD-L1 blockade and need to be validated on a larger patient series.
Role of Purinergic Receptor (P2X4) in EtOH-Mediated Microglial Immune ResponsesPotula, Raghava; Ramirez, Servio H.; Unterwald, Ellen M.; Sawaya, Bassel E.; Jordan-Sciutto, Kelly L. (Temple University. Libraries, 2015)Ethanol (EtOH) abuse is the third leading cause of preventable death in the United States. Mounting evidence indicates that EtOH-induced neuropathology may result from multicellular responses in which microglia cells play a prominent role. Purinergic receptor signaling plays a key role in regulating microglial function and, more importantly, mediates EtOH-induced effects. In our current study we sought to determine the effects of EtOH on microglial cell function, specifically the role of purinergic receptor X4 (P2X4) in EtOH-mediated microglial responses. Our results show a significant up-regulation of P2X4 gene expression as analyzed by real-time qPCR and protein expression as analyzed by flow cytometry in embryonic stem cell-derived microglial cells (ESdM) after 48 hours of EtOH treatment, as compared to untreated controls. Calcium mobilization in EtOH treated ESdM cells was found to be P2X4R- dependent using 5-BDBD, a selective P2X4R antagonist. Blocking P2X4R signaling with 5-BDBD decreased the level of calcium mobilization compared to EtOH treatment alone. EtOH decreased migration of microglia towards fractalkine (CX3CL1) by 75% following 48 hours of treatment compared to control. CX3CL1-dependent migration was confirmed to be P2X4 receptor-dependent using the antagonist 5-BDBD, which reversed the effects as compared to EtOH alone. Similarly, 48 hours of EtOH treatment significantly decreased phagocytosis of microglia by 15% compared to control. 5-BDBD pre-treatment prior to EtOH treatment significantly increased microglial phagocytosis. These findings demonstrate that P2X4 receptor may play a role in modulating important regulatory functions in microglia in the context of EtOH abuse. P2X4R plays an important regulatory function in microglia. P2X4 is involved in a myriad of molecular signaling such as proliferation, activation of transcription factors, specifically through the MAPK pathway, and ATP signaling. Here, we also investigated the intracellular signal transduction pathway that influences P2X4R expression in microglia in response to EtOH. We found EtOH (100 mM) decreased phosphorylated AKT and extracellular signal-regulated kinase (ERK) cascades in ESdM cells. EtOH effect on ERK phosphorylation was completely inhibited by U0126, an inhibitor of MEK 1 and 2. However, PD98095, a potent inhibitor of MEK1 but a weak inhibitor of MEK2 had modest effect on phosphorylated ERK1/2 suggesting a possible role of MEK2-dependent ERK signaling in modulating EtOH induced effects on microglia. Utilization of 5-BDBD, a selective P2X4R antagonist reversed the EtOH-induced effect on phosphorylated AKT and ERK. Next we wanted to examine the effects of EtOH on transcription factor activity to determine the signaling mediators, which may play a role in EtOH-induced increase in P2X4R in microglia. EtOH increased transcriptional activity of NFκB, NFAT, and CREB,, however 5-BDBD blocked the effect on CREB transcriptional activity alone, suggesting a specific role of CREB in EtOH-induced expression of P2X4R in microglia. In summary, EtOH affects the expression of P2X4R in microglial cells and contributes to aberrant microglial effector function including phagocytosis and migration as well as alterations in calcium mobilization. Furthermore, pharmacological blockade with a selective P2X4R antagonist reversed the action, suggesting that P2X4R may play a role in mediating EtOH-induced effects on microglia. EtOH decreased expression of ERK and AKT, which was blocked with the P2X4R antagonist, suggesting EtOH effect may contribute to irregular microglial signaling. Investigations regarding transcription factor NFκB, NFAT and CREB activity in response to EtOH, all showed an increase after EtOH treatment, however P2X4R antagonist only had an effect on CREB, blocking the effect of EtOH on its activity. Determining the mechanism underlying EtOH-induced increase in P2X4R expression still remains unclear. This research was conducted to investigate the importance of P2X4R signaling in EtOH-mediate microglial function. Although many more questions remain unanswered, these experiments have provided evidence to target purinergic receptor X4 as a potential mediator of EtOH-induced effects in microglia.