scholarly journals Gasdermin D activity in inflammation and host defense

2019 ◽  
Vol 4 (39) ◽  
pp. eaav1447 ◽  
Author(s):  
Judy Lieberman ◽  
Hao Wu ◽  
Jonathan C. Kagan
Keyword(s):  
Host Defense ◽  
Pore Formation ◽  
Therapeutic Potential ◽  
Interleukin 1 ◽  
Cell Fates ◽  
Secretion Signal ◽  
Amino Terminal ◽  
Distinct Cell ◽  
The Subject ◽  
Inflammatory Caspases

The mechanisms underlying the release of interleukin-1 (IL-1) family cytokines from phagocytes have been the subject of intense investigations for more than 30 years. The absence of an amino-terminal secretion signal from members of this family suggests a previously unknown mechanism of protein secretion that transfers cytosolic IL-1 directly across the plasma membrane into the extracellular space. The pore-forming protein gasdermin D (GSDMD) has emerged as the conduit for IL-1 secretion from the cytosol, serving to induce the release of IL-1 from living (hyperactive) or dead (pyroptotic) cells. In this Review, we discuss the mechanism by which GSDMD pore formation is regulated by the activity of inflammatory caspases, which are commonly associated with inflammasomes. We discuss how GSDMD promotes IL-1 release from hyperactive or pyroptotic cells, with a specific focus on defining how these distinct cell fates associated with GSDMD activity can be regulated. Last, the physiological consequences of GSDMD activity and therapeutic potential of targeting this pore-forming protein are discussed, which highlight the abundance of questions that remain to be answered by the community.

scholarly journals NF-κB in Cancer Immunity: Friend or Foe?

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 355
Author(s):  
Guilhem Lalle ◽  
Julie Twardowski ◽  
Yenkel Grinberg-Bleyer
Keyword(s):  
Immune Responses ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Transcriptional Activators ◽  
New Class ◽  
Complex Interactions ◽  
Cancer Immunity ◽  
Distinct Cell ◽  
Cancer Initiation ◽  
Cancer Outcome

The emergence of immunotherapies has definitely proven the tight relationship between malignant and immune cells, its impact on cancer outcome and its therapeutic potential. In this context, it is undoubtedly critical to decipher the transcriptional regulation of these complex interactions. Following early observations demonstrating the roles of NF-κB in cancer initiation and progression, a series of studies converge to establish NF-κB as a master regulator of immune responses to cancer. Importantly, NF-κB is a family of transcriptional activators and repressors that can act at different stages of cancer immunity. In this review, we provide an overview of the selective cell-intrinsic contributions of NF-κB to the distinct cell types that compose the tumor immune environment. We also propose a new view of NF-κB targeting drugs as a new class of immunotherapies for cancer.

scholarly journals The Potential Therapeutic Agent Mepacrine Protects Caco-2 Cells against Clostridium perfringens Enterotoxin Action

mSphere ◽  
2017 ◽  
Vol 2 (4) ◽  
Author(s):  
John C. Freedman ◽  
Matthew R. Hendricks ◽  
Bruce A. McClane
Keyword(s):  
Clostridium Perfringens ◽  
Pore Formation ◽  
Therapeutic Potential ◽  
Food Poisoning ◽  
Host Cells ◽  
Artificial Membranes ◽  
Content Type ◽  
Gi Symptoms ◽  
Human Enterocyte ◽  
Bacterial Food

ABSTRACT Clostridium perfringens enterotoxin (CPE) causes the gastrointestinal (GI) symptoms of a common bacterial food poisoning and several nonfoodborne human GI diseases. A previous study showed that, via an undetermined mechanism, the presence of mepacrine blocks CPE-induced electrophysiologic activity in artificial membranes. The current study now demonstrates that mepacrine also inhibits CPE-induced cytotoxicity in human enterocyte-like Caco-2 cells and that mepacrine does not directly inactivate CPE. Instead, this drug reduces both CPE pore formation and CPE pore activity in Caco-2 cells. These results suggest mepacrine as a therapeutic candidate for treating CPE-mediated GI diseases. Clostridium perfringens enterotoxin (CPE) causes the diarrhea associated with a common bacterial food poisoning and many antibiotic-associated diarrhea cases. The severity of some CPE-mediated disease cases warrants the development of potential therapeutics. A previous study showed that the presence of mepacrine inhibited CPE-induced electrophysiology effects in artificial lipid bilayers lacking CPE receptors. However, that study did not assess whether mepacrine inactivates CPE or, instead, inhibits a step in CPE action. Furthermore, CPE action in host cells is complex, involving the toxin binding to receptors, receptor-bound CPE oligomerizing into a prepore on the membrane surface, and β-hairpins in the CPE prepore inserting into the membrane to form a pore that induces cell death. Therefore, the current study evaluated the ability of mepacrine to protect cells from CPE. This drug was found to reduce CPE-induced cytotoxicity in Caco-2 cells. This protection did not involve mepacrine inactivation of CPE, indicating that mepacrine affects one or more steps in CPE action. Western blotting then demonstrated that mepacrine decreases CPE pore levels in Caco-2 cells. This mepacrine-induced reduction in CPE pore levels did not involve CPE binding inhibition but rather an increase in CPE monomer dissociation due to mepacrine interactions with Caco-2 membranes. In addition, mepacrine was also shown to inhibit CPE pores when already present in Caco-2 cells. These in vitro studies, which identified two mepacrine-sensitive steps in CPE-induced cytotoxicity, add support to further testing of the therapeutic potential of mepacrine against CPE-mediated disease. IMPORTANCE Clostridium perfringens enterotoxin (CPE) causes the gastrointestinal (GI) symptoms of a common bacterial food poisoning and several nonfoodborne human GI diseases. A previous study showed that, via an undetermined mechanism, the presence of mepacrine blocks CPE-induced electrophysiologic activity in artificial membranes. The current study now demonstrates that mepacrine also inhibits CPE-induced cytotoxicity in human enterocyte-like Caco-2 cells and that mepacrine does not directly inactivate CPE. Instead, this drug reduces both CPE pore formation and CPE pore activity in Caco-2 cells. These results suggest mepacrine as a therapeutic candidate for treating CPE-mediated GI diseases.

scholarly journals Amino Terminal Recognition by a CCR6 Chemokine Receptor Antibody Blocks CCL20 Signaling and IL-17 Expression via β-arrestin

2021 ◽  
Author(s):  
Sara Gómez-Melero ◽  
Fé Isabel García-Maceira ◽  
Tania García-Maceira ◽  
Verónica Luna-Guerrero ◽  
Gracia Montero-Peñalvo ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Flow Cytometry ◽  
Chemokine Receptor ◽  
Th17 Cells ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Specific Binding ◽  
Isolation And Purification ◽  
Amino Terminal ◽  
Important Target

Abstract Background: CCR6 chemokine receptor is an important target in inflammatory diseases. Th17 cells express CCR6 and a number of inflammatory cytokines, including IL-17 and IL-22, which are involved in the propagation of inflammatory immune responses. CCR6 antagonist would be a potential treatment for inflammatory diseases such as psoriasis or rheumatoid arthritis. The aim of this study is to develop an antagonistic monoclonal antibody (mAb) against human CCR6 receptor (hCCR6).Results: We generate monoclonal antibodies against hCCR6 immunizing Balb/c mice with hCCR6 overexpressing cells. The antibodies were tested by flow cytometry for specific binding to hCCR6, cloned by limiting dilution and resulted in the isolation and purification monoclonal antibody 1C6. By ELISA and flow cytometry, was determined that the antibody obtained binds to hCCR6 N-terminal domain. The ability of 1C6 to neutralize hCCR6 signaling was tested and we determined that 1C6 antibody were able to block response in β-arrestin recruitment assay with IC50 10.23 nM, but did not inhibit calcium mobilization. In addition, we found in a chemotaxis assay that 1C6 reduces the migration of hCCR6 cells to their ligand CCL20. Finally, we determined by RT-qPCR that the expression of IL-17A in Th17 cells treated with 1C6 was inhibited.Conclusions: In the present study, we applied whole cell immunization for successfully obtain an antibody that is capable to neutralize hCCR6 signaling and to reduce hCCR6 cells migration and IL-17 expression. These results provide an efficient approach to obtain therapeutic potential antibodies in the treatment of CCR6-mediated inflammatory diseases.

scholarly journals An Amino-Terminal Secretion Signal Is Required for YplA Export by the Ysa, Ysc, and Flagellar Type III Secretion Systems of Yersinia enterocolitica Biovar 1B

2005 ◽  
Vol 187 (17) ◽  
pp. 6075-6083 ◽  
Author(s):  
Sasha M. Warren ◽  
Glenn M. Young
Keyword(s):  
Yersinia Enterocolitica ◽  
Type Iii Secretion ◽  
Distinct Type ◽  
Host Cells ◽  
Amino Acid Residues ◽  
Secretion Systems ◽  
Type Iii ◽  
Secretion Signal ◽  
Amino Terminal ◽  
Type Iii Secretion Systems

ABSTRACT Yersinia enterocolitica biovar 1B maintains three distinct type III secretion (TTS) systems, which independently operate to target proteins to extracellular sites. The Ysa and Ysc systems are prototypical contact-dependent TTS systems that translocate toxic effectors to the cytosols of targeted eukaryotic host cells during infection. The flagellar TTS system is utilized during the assembly of the flagellum and is required for secretion of the virulence-associated phospholipase YplA to the bacterial milieu. When ectopically produced, YplA is also a secretion substrate for the Ysa and Ysc TTS systems. In this study, we define elements that allow YplA recognition and export by the Ysa, Ysc, and flagellar TTS systems. Fusion of various amino-terminal regions of YplA to Escherichia coli alkaline phosphatase (PhoA) lacking its native secretion signal demonstrated that the first 20 amino acids or corresponding mRNA codons of YplA were sufficient for export of YplA-PhoA chimeras by each TTS system. Export of native YplA by each of the three TTS systems was also found to depend on the integrity of its amino terminus. Introduction of a frameshift mutation or deletion of yplA sequences encoding the amino-terminal 20 residues negatively impacted YplA secretion. Deletion of other yplA regions was tolerated, including that resulting in the removal of amino acid residues 30 through 40 of the polypeptide and removal of the 5′ untranslated region of the mRNA. This work supports a model in which independent and distantly related TTS systems of Y. enterocolitica recognize protein substrates by a similar mechanism.

scholarly journals Therapeutic potential of intermittent hypoxia: a matter of dose

2014 ◽  
Vol 307 (10) ◽  
pp. R1181-R1197 ◽  
Author(s):  
Angela Navarrete-Opazo ◽  
Gordon S. Mitchell
Keyword(s):  
Intermittent Hypoxia ◽  
Therapeutic Potential ◽  
Therapeutic Effects ◽  
Extensive Literature ◽  
Beneficial Effects ◽  
Metabolic Bone ◽  
Clinical Disorders ◽  
The Subject ◽  
Critical Characteristics ◽  
The Impact

Intermittent hypoxia (IH) has been the subject of considerable research in recent years, and triggers a bewildering array of both detrimental and beneficial effects in multiple physiological systems. Here, we review the extensive literature concerning IH and its impact on the respiratory, cardiovascular, immune, metabolic, bone, and nervous systems. One major goal is to define relevant IH characteristics leading to safe, protective, and/or therapeutic effects vs. pathogenesis. To understand the impact of IH, it is essential to define critical characteristics of the IH protocol under investigation, including potentially the severity of hypoxia within episodes, the duration of hypoxic episodes, the number of hypoxic episodes per day, the pattern of presentation across time (e.g., within vs. consecutive vs. alternating days), and the cumulative time of exposure. Not surprisingly, severe/chronic IH protocols tend to be pathogenic, whereas any beneficial effects are more likely to arise from modest/acute IH exposures. Features of the IH protocol most highly associated with beneficial vs. pathogenic outcomes include the level of hypoxemia within episodes and the number of episodes per day. Modest hypoxia (9–16% inspired O2) and low cycle numbers (3–15 episodes per day) most often lead to beneficial effects without pathology, whereas severe hypoxia (2–8% inspired O2) and more episodes per day (48–2,400 episodes/day) elicit progressively greater pathology. Accumulating evidence suggests that “low dose” IH (modest hypoxia, few episodes) may be a simple, safe, and effective treatment with considerable therapeutic potential for multiple clinical disorders.

scholarly journals STING Signaling Promotes Apoptosis, Necrosis, and Cell Death: An Overview and Update

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Song Liu ◽  
Wenxian Guan
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Tumor Immunity ◽  
Host Defense ◽  
Cell Types ◽  
Immune Homeostasis ◽  
Induce Cell Death ◽  
Distinct Cell ◽  
Clinical Strategies ◽  
Apoptosis And Necrosis

STING is a newly identified intracellular sensor of foreign and endogenous DNA. STING has been recognized as an activator of immune responses by TBK1/IRF3 and NF-κB pathways, and it is suggested to play critical roles in host defense, autoimmune diseases, and tumor immunity. Recent studies have revealed that the outcome of STING activation could vary between distinct cell types and scenarios. STING activation in certain cell types triggered cell death including apoptosis and necrosis. This effect could be critical for preventing unnecessary or excessive inflammatory events and maintaining host immune homeostasis. This review is dedicated to summarize recent evidences in the field of STING-mediated cell death and to demonstrate dual outcomes of STING signaling. Besides canonical immune responses represented by IFN and TNF productions, STING signaling can also induce cell death events in a variety of cell types. The double-faced characteristics of STING signaling requires further exploration and precious regulation before tailoring clinical strategies for associated diseases.

Sign in / Sign up

Export Citation Format

Share Document