bims-inflin Biomed News
on Inflammasome and infection
Issue of 2023–11–26
six papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto
  1. Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion.
  2. SARS-CoV-2 Papain-like Protease Negatively Regulates the NLRP3 Inflammasome Pathway and Pyroptosis by Reducing the Oligomerization and Ubiquitination of ASC.
  3. P2X7 receptor activation leads to NLRP3-independent IL-1β release by human macrophages.
  4. Gasdermin D is the only Gasdermin that provides protection against acute Salmonella gut infection in mice.
  5. SARS-CoV-2 nucleocapsid protein promotes TMAO-induced NLRP3 inflammasome activation by SCAP-SREBP signaling pathway.
  6. NINJ1 is activated by cell swelling to regulate plasma membrane permeabilization during regulated necrosis.
  1. Sci Immunol. 2023 Nov 24. 8(89): eadf4404
    Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion.
    M Giulia Doglio, Lien Verboom, Emily Ruilova Sosoranga, Ulrika C Frising, Tomoko Asaoka, Yannick Gansemans, Filip Van Nieuwerburgh, Geert van Loo, Andy Wullaert.
      Loss-of-function mutations in the deubiquitinase OTULIN result in an inflammatory pathology termed "OTULIN-related autoinflammatory syndrome" (ORAS). Genetic mouse models revealed essential roles for OTULIN in inflammatory and cell death signaling, but the mechanisms by which OTULIN deficiency connects cell death to inflammation remain unclear. Here, we identify OTULIN deficiency as a cellular condition that licenses RIPK3-mediated cell death in murine macrophages, leading to Nlrp3 inflammasome activation and subsequent IL-1β secretion. OTULIN deficiency uncoupled Nlrp3 inflammasome activation from gasdermin D-mediated pyroptosis, instead allowing RIPK3-dependent cell death to act as an Nlrp3 inflammasome activator and mechanism for IL-1β release. Accordingly, elevated serum IL-1β levels in myeloid-specific OTULIN-deficient mice were diminished by deleting either Ripk3 or Nlrp3. These findings identify OTULIN as an inhibitor of RIPK3-mediated IL-1β release in mice.
    DOI:  https://doi.org/10.1126/sciimmunol.adf4404
  2. Microorganisms. 2023 Nov 17. pii: 2799. [Epub ahead of print]11(11):
    SARS-CoV-2 Papain-like Protease Negatively Regulates the NLRP3 Inflammasome Pathway and Pyroptosis by Reducing the Oligomerization and Ubiquitination of ASC.
    Huan Meng, Jianglin Zhou, Mingyu Wang, Mei Zheng, Yaling Xing, Yajie Wang.
      The interaction of viruses with hosts is complex, especially so with the antiviral immune systems of hosts, and the underlying mechanisms remain perplexing. Infection with SARS-CoV-2 may result in cytokine syndrome in the later stages, reflecting the activation of the antiviral immune response. However, viruses also encode molecules to negatively regulate the antiviral immune systems of hosts to achieve immune evasion and benefit viral replication during the early stage of infection. It has been observed that the papain-like protease (PLP) encoded by coronavirus could negatively regulate the host's IFNβ innate immunity. In this study, we first found that eight inflammasome-related genes were downregulated in CD14+ monocytes from COVID-19 patients. Subsequently, we observed that SARS-CoV-2 PLP negatively regulated the NLRP3 inflammasome pathway, inhibited the secretion of IL-1β, and decreased the caspase-1-mediated pyroptosis of human monocytes. The mechanisms for this may arise because PLP coimmunoprecipitates with ASC, reduces ASC ubiquitination, and inhibits ASC oligomerization and the formation of ASC specks. These findings suggest that PLP may inhibit strong immune defenses and provide the maximum advantage for viral replication. This research may allow us to better understand the flex function of CoV-encoding proteases and provide a new perspective on the innate immune responses against SARS-CoV-2 and other viruses.
    Keywords:  ASC; IL-1β; NLRP3 inflammasome; SARS-CoV-2; deubiquitination; papain-like protease; pyroptosis
    DOI:  https://doi.org/10.3390/microorganisms11112799
  3. Cell Commun Signal. 2023 Nov 23. 21(1): 335
    P2X7 receptor activation leads to NLRP3-independent IL-1β release by human macrophages.
    Judith Bockstiegel, Jonas Engelhardt, Günther Weindl.
       BACKGROUND: The purinergic receptor P2X7 plays a crucial role in infection, inflammation, and cell death. It is thought that P2X7 receptor stimulation triggers processing and release of the pro-inflammatory cytokine interleukin (IL)-1β by activation of the NLRP3 inflammasome; however, the underlying mechanisms remain poorly understood.
    METHODS: Modulation of IL-1β secretion was studied in THP-1 macrophages. Adenosine 5'-triphosphate (ATP), BzATP, nigericin and pharmacological inhibitors of P2X receptors, inflammatory caspases and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome were used to characterize signaling.
    RESULTS: In primed macrophages, IL-1β release was increased after P2X7 receptor activation by ATP and 2,3-O-(4-benzoylbenzoyl)-ATP (BzATP). Pharmacological inhibition or genetic knockout of NLRP3 does not completely inhibit IL-1β release in TLR2/1-primed macrophages. Increase in extracellular K+ as well as inhibition of caspase-1 or serine proteases maintained IL-1β release in macrophages stimulated with P2X7 receptor agonists at 50%.
    CONCLUSIONS: Our findings suggest a previously unrecognized mechanism of P2X7 receptor mediated IL-1β release and highlight the existence of an NLRP3-independent pathway in human macrophages. Video Abstract.
    Keywords:  Human macrophages; IL-1beta; NLRP3 inflammasome; P2X7 receptor; Toll-like receptors
    DOI:  https://doi.org/10.1186/s12964-023-01356-1
  4. Proc Natl Acad Sci U S A. 2023 Nov 28. 120(48): e2315503120
    Gasdermin D is the only Gasdermin that provides protection against acute Salmonella gut infection in mice.
    Stefan A Fattinger, Luca Maurer, Petra Geiser, Elliott M Bernard, Ursina Enz, Suwannee Ganguillet, Ersin Gül, Sanne Kroon, Benjamin Demarco, Vanessa Mack, Markus Furter, Manja Barthel, Pawel Pelczar, Feng Shao, Petr Broz, Mikael E Sellin, Wolf-Dietrich Hardt.
      Gasdermins (GSDMs) share a common functional domain structure and are best known for their capacity to form membrane pores. These pores are hallmarks of a specific form of cell death called pyroptosis and mediate the secretion of pro-inflammatory cytokines such as interleukin 1β (IL1β) and interleukin 18 (IL18). Thereby, Gasdermins have been implicated in various immune responses against cancer and infectious diseases such as acute Salmonella Typhimurium (S.Tm) gut infection. However, to date, we lack a comprehensive functional assessment of the different Gasdermins (GSDMA-E) during S.Tm infection in vivo. Here, we used epithelium-specific ablation, bone marrow chimeras, and mouse lines lacking individual Gasdermins, combinations of Gasdermins or even all Gasdermins (GSDMA1-3C1-4DE) at once and performed littermate-controlled oral S.Tm infections in streptomycin-pretreated mice to investigate the impact of all murine Gasdermins. While GSDMA, C, and E appear dispensable, we show that GSDMD i) restricts S.Tm loads in the gut tissue and systemic organs, ii) controls gut inflammation kinetics, and iii) prevents epithelium disruption by 72 h of the infection. Full protection requires GSDMD expression by both bone-marrow-derived lamina propria cells and intestinal epithelial cells (IECs). In vivo experiments as well as 3D-, 2D-, and chimeric enteroid infections further show that infected IEC extrusion proceeds also without GSDMD, but that GSDMD controls the permeabilization and morphology of the extruding IECs, affects extrusion kinetics, and promotes overall mucosal barrier capacity. As such, this work identifies a unique multipronged role of GSDMD among the Gasdermins for mucosal tissue defense against a common enteric pathogen.
    Keywords:  immunology; microbiology; pathogen; pyroptosis
    DOI:  https://doi.org/10.1073/pnas.2315503120
  5. Tissue Cell. 2023 Nov 15. pii: S0040-8166(23)00264-1. [Epub ahead of print]86 102276
    SARS-CoV-2 nucleocapsid protein promotes TMAO-induced NLRP3 inflammasome activation by SCAP-SREBP signaling pathway.
    Mi-Hua Liu, Xiao-Long Lin, Le-Le Xiao.
      The sterol regulatory element-binding protein (SREBP) activation and cytokine level were significantly increased in coronavirus disease-19. The NLRP3 inflammasome is an amplifier for cellular inflammation. This study aimed to elucidate the modulatory effect of SARS-CoV-2 nucleocapsid protein (SARS-CoV-2 NP) on trimethylamine N-oxide (TMAO)-induced lipogenesis and NLRP3 inflammasome activation and the underlying mechanisms in vascular smooth muscle cells (VSMCs). Our data indicated that SARS-CoV-2 NP activates the dissociation of the SREBP cleavage activating protein (SCAP) from the endoplasmic reticulum, resulting in SREBP activation, increased lipogenic gene expression, and NLRP3 inflammasome activation. TMAO was applied to VSMC-induced NLRP3 inflammasome by promoting the SCAP-SREBP complex endoplasmic reticulum-to-Golgi translocation, which facilitates directly binding of SARS-CoV-2 NP to the NLRP3 protein for NLRP3 inflammasome assembly. SARS-CoV-2 NP amplified the TMAO-induced lipogenic gene expression and NLRP3 inflammasome. Knockdown of SCAP-SREBP2 can effectively reduce lipogenic gene expression and alleviate NLRP3 inflammasome-mediated systemic inflammation in VSMCs stimulated with TMAO and SARS-CoV-2 NP. These results reveal that SARS-CoV-2 NP amplified TMAO-induced lipogenesis and NLRP3 inflammasome activation via priming the SCAP-SREBP signaling pathway.
    Keywords:  COVID-19; Inflammasome; SARS-CoV-2 NP; SCAP; SREBPs; Vascular smooth muscle cell
    DOI:  https://doi.org/10.1016/j.tice.2023.102276
  6. Cell Death Dis. 2023 11 18. 14(11): 755
    NINJ1 is activated by cell swelling to regulate plasma membrane permeabilization during regulated necrosis.
    Yves Dondelinger, Dario Priem, Jon Huyghe, Tom Delanghe, Peter Vandenabeele, Mathieu J M Bertrand.
      Plasma membrane permeabilization (PMP) is a defining feature of regulated necrosis. It allows the extracellular release of damage-associated molecular patterns (DAMPs) that trigger sterile inflammation. The pore forming molecules MLKL and GSDMs drive PMP in necroptosis and pyroptosis, respectively, but the process of PMP remains unclear in many other forms of regulated necrosis. Here, we identified NINJ1 as a crucial regulator of PMP and consequent DAMP release during ferroptosis, parthanatos, H2O2-induced necrosis and secondary necrosis. Importantly, the membrane-permeabilizing function of NINJ1 takes place after the metabolic death of the cells and is independent of the pore-forming molecules MLKL, GSDMD and GSDME. During ferroptosis, NINJ1 acts downstream of lipid peroxidation, which suggested a role for reactive oxygen species (ROS) in NINJ1 activation. Reactive oxygen species were however neither sufficient nor required to trigger NINJ1-dependent PMP. Instead, we found that NINJ1 oligomerization is induced by the swelling of the cell and that its permeabilizing potential still requires an addition, and yet to be discovered, activation mechanism.
    DOI:  https://doi.org/10.1038/s41419-023-06284-z
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