scholarly journals Gasdermins and their role in immunity and inflammation

2019 ◽  
Vol 216 (11) ◽  
pp. 2453-2465 ◽  
Author(s):  
Pontus Orning ◽  
Egil Lien ◽  
Katherine A. Fitzgerald
Keyword(s):  
Septic Shock ◽  
Immune Response ◽  
Cell Death ◽  
Autoimmune Diseases ◽  
Proinflammatory Cytokines ◽  
Mechanism Of Action ◽  
Drug Target ◽  
Biological Significance ◽  
Pore Forming Proteins ◽  
Related Proteins

The gasdermins are a family of pore-forming proteins recently implicated in the immune response. One of these proteins, gasdermin D (GSDMD), has been identified as the executioner of pyroptosis, an inflammatory form of lytic cell death that is induced upon formation of caspase-1–activating inflammasomes. The related proteins GSDME and GSDMA have also been implicated in autoimmune diseases and certain cancers. Most gasdermin proteins are believed to have pore-forming capabilities. The best-studied member, GSDMD, controls the release of the proinflammatory cytokines IL-1ß and IL-18 and pyroptotic cell death. Because of its potential as a driver of inflammation in septic shock and autoimmune diseases, GSDMD represents an attractive drug target. In this review, we discuss the gasdermin proteins with particular emphasis on GSDMD and its mechanism of action and biological significance.

Blockage of Fc Gamma Receptors Alleviates Neuronal and Microglial Toxicity Induced by Palmitic Acid

2021 ◽  
pp. 1-18
Author(s):  
Phansa Phitthayaphong ◽  
Sirinart Kumfu ◽  
Nipon Chattipakorn ◽  
Siriporn C. Chattipakorn
Keyword(s):  
Cell Death ◽  
Cell Viability ◽  
Palmitic Acid ◽  
Proinflammatory Cytokines ◽  
Microglial Activation ◽  
Cell Types ◽  
Brain Cell ◽  
Signaling Proteins ◽  
Fc Gamma Receptors ◽  
Related Proteins

Background: Palmitic acid (PA) promotes brain pathologies including Alzheimer’s disease (AD)-related proteins, neuroinflammation, and microglial activation. The activation of neurons and microglia via their Fc gamma receptors (FcγRs) results in producing inflammatory cytokines. Objective: To investigate the expression of FcγRs, FcγR signaling proteins, AD-related proteins, proinflammatory cytokines, and cell viability of neurons and microglia in association with PA exposure as well as the effects of FcγR blockade on these parameters in response to PA. Methods: 200 and 400μM PA-conjugated BSA were applied to SH-SY5Y and HMC3 cells for 24 h. For FcγR blockage experiment, both cells were exposed to FcγR blocker before receiving of 200 and 400μM of PA-conjugated BSA for 24 h. Results: PA significantly increased AD-related proteins, including Aβ and BACE1, as well as increasing TNFα, IL-1β, and IL-6 in SH-SY5Y and HMC3 cells. However, the p-Tau/Tau ratio was only increased in SH-SY5Y cells. These results were associated with an increase in FcγRs activation and a decrease in cell viability in both cell types. FcγRs blockage diminished the activation of FcγR in SH-SY5Y and HMC3 cells. Interestingly, blocking FcγRs before PA exposure reduced the increment of AD-related proteins, proinflammatory cytokines caused by PA. FcγRs blocking also inhibits cell death for 23%of SH-SY5Y cells and 64%of HMC3 cells, respectively. Conclusion: These findings suggest that PA is a risk factor for AD via the increased AD-related pathologies, inflammation, FcγRs activation, and brain cell death, while FcγR blockage can alleviate these effects.

scholarly journals Antigen-Experienced CD4lo T Cells Are Linked to Deficient Contraction of the Immune Response in Autoimmune Diabetes

2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
Author(s):  
Sean Linkes ◽  
Christopher Fry ◽  
Anthony Quinn
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Effector T Cells ◽  
Activation Induced Cell Death ◽  
Enhanced Expression

Following proper activation, naïve “CD4lo” T cells differentiate into effector T cells with enhanced expression of CD4 -“CD4hi” effectors. Autoimmune diabetes-prone NOD mice display a unique set of antigen-experienced “CD4lo” T cells that persist after primary stimulation. Here, we report that a population of such cells remained after secondary and tertiary TCR stimulation and produced cytokines upon antigenic challenge. However, when NOD blasts were induced in the presence of rIL-15, the number of antigen-experienced “CD4lo” T cells was significantly reduced. Clonal contraction, mediated in part by CD95-dependent activation-induced cell death (AICD), normally regulates the accumulation of “CD4hi” effectors. Interestingly, CD95 expression was dramatically reduced on the AICD-resistant NOD “CD4lo” T cells. Thus, while autoimmune disease has often been attributed to the engagement of robust autoimmunity, we suggest that the inability to effectively contract the immune response distinguishes benign autoimmunity from progressive autoimmune diseases that are characterized by chronic T cell-mediated inflammation.

scholarly journals Progress in understanding the role of lncRNA in programmed cell death

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Na Jiang ◽  
Xiaoyu Zhang ◽  
Xuejun Gu ◽  
Xiaozhuang Li ◽  
Lei Shang
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Membrane Receptors ◽  
Gene Expressions ◽  
Apoptosis Pathway ◽  
Stem Cell Pluripotency ◽  
Extrinsic Apoptosis ◽  
Related Proteins ◽  
Cycle Regulation

AbstractLong non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but not translated into proteins. LncRNAs regulate gene expressions at multiple levels, such as chromatin, transcription, and post-transcription. Further, lncRNAs participate in various biological processes such as cell differentiation, cell cycle regulation, and maintenance of stem cell pluripotency. We have previously reported that lncRNAs are closely related to programmed cell death (PCD), which includes apoptosis, autophagy, necroptosis, and ferroptosis. Overexpression of lncRNA can suppress the extrinsic apoptosis pathway by downregulating of membrane receptors and protect tumor cells by inhibiting the expression of necroptosis-related proteins. Some lncRNAs can also act as competitive endogenous RNA to prevent oxidation, thereby inhibiting ferroptosis, while some are known to activate autophagy. The relationship between lncRNA and PCD has promising implications in clinical research, and reports have highlighted this relationship in various cancers such as non-small cell lung cancer and gastric cancer. This review systematically summarizes the advances in the understanding of the molecular mechanisms through which lncRNAs impact PCD.

scholarly journals ZBP1 promotes LPS-induced cell death and IL-1β release via RHIM-mediated interactions with RIPK1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hayley I. Muendlein ◽  
Wilson M. Connolly ◽  
Zoie Magri ◽  
Irina Smirnova ◽  
Vladimir Ilyukha ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Complex Formation ◽  
Complex I ◽  
Yersinia Pseudotuberculosis ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Inflammatory Signaling ◽  
Complex Ii ◽  
Dependent Model

AbstractInflammation and cell death are closely linked arms of the host immune response to infection, which when carefully balanced ensure host survival. One example of this balance is the tightly regulated transition from TNFR1-associated pro-inflammatory complex I to pro-death complex II. By contrast, here we show that a TRIF-dependent complex containing FADD, RIPK1 and caspase-8 (that we have termed the TRIFosome) mediates cell death in response to Yersinia pseudotuberculosis and LPS. Furthermore, we show that constitutive binding between ZBP1 and RIPK1 is essential for the initiation of TRIFosome interactions, caspase-8-mediated cell death and inflammasome activation, thus positioning ZBP1 as an effector of cell death in the context of bacterial blockade of pro-inflammatory signaling. Additionally, our findings offer an alternative to the TNFR1-dependent model of complex II assembly, by demonstrating pro-death complex formation reliant on TRIF signaling.

scholarly journals Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma

2021 ◽  
Vol 9 (2) ◽  
pp. e001696
Author(s):  
Yi Que ◽  
Xiao-Long Zhang ◽  
Ze-Xian Liu ◽  
Jing-Jing Zhao ◽  
Qiu-Zhong Pan ◽  
...  
Keyword(s):  
Cell Death ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Programmed Cell Death ◽  
Gene Family ◽  
Murine Model ◽  
Immune Checkpoint ◽  
Drug Target ◽  
Class I ◽  
Mechanistic Study

BackgroundThe advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival.MethodsWhole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study.ResultsThe HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1.ConclusionsThe combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

scholarly journals Polyglandular Autoimmune Syndrome Triggered after CTLA-4 and PD-1L Immunotherapy Treatment

Reports ◽  
2021 ◽  
Vol 4 (1) ◽  
pp. 1
Author(s):  
Juan Luis Fernández-Morera ◽  
Alfredo Renilla González ◽  
Carmen Elena Calvo Rodríguez ◽  
Judit Romano-García
Keyword(s):  
Immune Response ◽  
Side Effects ◽  
Autoimmune Diseases ◽  
Autoimmune Diabetes ◽  
Hashimoto Thyroiditis ◽  
Polyglandular Autoimmune Syndrome ◽  
Autoimmune Syndrome ◽  
Previous Diagnosis ◽  
Optimal Approach

Background: CTLA-4 and PD-1L are novel immune checkpoint targets for cancer treatment with specific side effects such as autoimmune diseases. Less frequently, the presence of several autoimmune diseases in the same patient has been described. In this communication, we illustrate the case of a 45-year-old patient with a previous diagnosis of advanced cancer that, after starting treatment with this immunotherapy, developed in the following months autoimmune diabetes, lymphocytic hypophysitis, and a Hashimoto thyroiditis in an abrupt and intense manner that would correspond to an autoimmune polyglandular disease. Discussion: The activation of autoimmunity and associated diseases is increasing in parallel with augmented indication of these immunotherapeutic treatments in cancer patients. A closer follow-up of these patients could be necessary for an optimal approach to this type of pathology. Conclusions: Different autoimmune diseases can converge in the same patient when immunotherapy for cancer is indicated to boost immune response against tumor, caused by altering immune tolerance.

scholarly journals IgA Vasculitis: Etiology, Treatment, Biomarkers and Epigenetic Changes

2021 ◽  
Vol 22 (14) ◽  
pp. 7538
Author(s):  
Hitomi Sugino ◽  
Yu Sawada ◽  
Motonobu Nakamura
Keyword(s):  
Immune Response ◽  
Autoimmune Diseases ◽  
Organ Dysfunction ◽  
Human Body ◽  
Therapeutic Approach ◽  
Viral Infections ◽  
External Environment ◽  
Iga Vasculitis ◽  
Epigenetic Changes ◽  
Flexible Response

IgA, previously called Henoch-Schönlein vasculitis, is an essential immune component that drives the host immune response to the external environment. As IgA has the unique characteristic of a flexible response to broad types of microorganisms, it sometimes causes an autoreactive response in the host human body. IgA vasculitis and related organ dysfunction are representative IgA-mediated autoimmune diseases; bacterial and viral infections often trigger IgA vasculitis. Recent drug developments and the presence of COVID-19 have revealed that these agents can also trigger IgA vasculitis. These findings provide a novel understanding of the pathogenesis of IgA vasculitis. In this review, we focus on the characteristics of IgA and symptoms of IgA vasculitis and other organ dysfunction. We also mention the therapeutic approach, biomarkers, novel triggers for IgA vasculitis, and epigenetic modifications in patients with IgA vasculitis.

scholarly journals Polymerized albumin restores impaired hemodynamics in endotoxemia and polymicrobial sepsis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Donald A. Belcher ◽  
Alexander T. Williams ◽  
Andre F. Palmer ◽  
Pedro Cabrales
Keyword(s):  
Septic Shock ◽  
Immune Response ◽  
Fluid Resuscitation ◽  
Cecal Ligation ◽  
Vascular Wall ◽  
Polymicrobial Sepsis ◽  
Vascular Integrity ◽  
Fluid Extravasation ◽  
Inflammatory Immune Response ◽  
Polymerized Human Serum Albumin

AbstractFluid resuscitation following severe inflammation-induced hypoperfusion is critical for the restoration of hemodynamics and the prevention of multiorgan dysfunction syndrome during septic shock. Fluid resuscitation with commercially available crystalloid and colloid solutions only provides transient benefits, followed by fluid extravasation and tissue edema through the inflamed endothelium. The increased molecular weight (M.W.) of polymerized human serum albumin (PolyHSA) can limit fluid extravasation, leading to restoration of hemodynamics. In this prospective study, we evaluated how fluid resuscitation with PolyHSA impacts the hemodynamic and immune response in a lipopolysaccharide (LPS) induced endotoxemia mouse model. Additionally, we evaluated fluid resuscitation with PolyHSA in a model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Resuscitation with PolyHSA attenuated the immune response and improved the maintenance of systemic hemodynamics and restoration of microcirculatory hemodynamics. This decrease in inflammatory immune response and maintenance of vascular wall shear stress likely contributes to the maintenance of vascular integrity following fluid resuscitation with PolyHSA. The sustained restoration of perfusion, decrease in pro-inflammatory immune response, and improved vascular integrity that results from the high M.W. of PolyHSA indicates that a PolyHSA based solution is a potential resuscitation fluid for endotoxic and septic shock.

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