bims-inflin Biomed News
on Inflammasome and infection
Issue of 2024–03–31
five papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto
  1. A bacterial toxin co-opts caspase-3 to disable active gasdermin D and limit macrophage pyroptosis.
  2. SLC25A3 negatively regulates NLRP3 inflammasome activation by restricting the function of NLRP3.
  3. Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation.
  4. A stress sensor, IRE1α, is required for bacterial-exotoxin-induced interleukin-1β production in tissue-resident macrophages.
  5. GLUT1 promotes NLRP3 inflammasome activation of airway epithelium in lipopolysaccharide-induced acute lung injury.
  1. Cell Rep. 2024 Mar 22. pii: S2211-1247(24)00332-2. [Epub ahead of print]43(4): 114004
    A bacterial toxin co-opts caspase-3 to disable active gasdermin D and limit macrophage pyroptosis.
    Skylar S Wright, Chengliang Wang, Atri Ta, Morena S Havira, Jianbin Ruan, Vijay A Rathinam, Sivapriya Kailasan Vanaja.
      During infections, host cells are exposed to pathogen-associated molecular patterns (PAMPs) and virulence factors that stimulate multiple signaling pathways that interact additively, synergistically, or antagonistically. The net effect of such higher-order interactions is a vital determinant of the outcome of host-pathogen interactions. Here, we demonstrate one such complex interplay between bacterial exotoxin- and PAMP-induced innate immune pathways. We show that two caspases activated during enterohemorrhagic Escherichia coli (EHEC) infection by lipopolysaccharide (LPS) and Shiga toxin (Stx) interact in a functionally antagonistic manner; cytosolic LPS-activated caspase-11 cleaves full-length gasdermin D (GSDMD), generating an active pore-forming N-terminal fragment (NT-GSDMD); subsequently, caspase-3 activated by EHEC Stx cleaves the caspase-11-generated NT-GSDMD to render it nonfunctional, thereby inhibiting pyroptosis and interleukin-1β maturation. Bacteria typically subvert inflammasomes by targeting upstream components such as NLR sensors or full-length GSDMD but not active NT-GSDMD. Thus, our findings uncover a distinct immune evasion strategy where a bacterial toxin disables active NT-GSDMD by co-opting caspase-3.
    Keywords:  CP: Immunology; CP: Microbiology; EHEC; Shiga toxin; caspase-11; caspase-3; enterohemorrhagic E. coli; gasdermin D; noncanonical inflammasome; pyroptosis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114004
  2. J Biol Chem. 2024 Mar 27. pii: S0021-9258(24)01730-7. [Epub ahead of print] 107233
    SLC25A3 negatively regulates NLRP3 inflammasome activation by restricting the function of NLRP3.
    Feng Xiao, Yaling Jia, Simeng Zhang, Nanfang Liu, Xuelong Zhang, Tianci Wang, Jialu Qiao, Ge Yang, Xu Che, Keli Chen, Pan Pan, Lingli Zhou, Binlian Sun, Jun Chen, Pin Wan.
      The NACHT, leucine-rich repeat, and pyrin domains-containing protein 3 (collectively known as NLRP3) inflammasome activation plays a critical role in innate immune and pathogenic microorganism infections. However, excessive activation of NLRP3 inflammasome will lead to cellular inflammation and tissue damage, and naturally it must be precisely controlled in the host. Here, we discovered that solute carrier family 25 member 3 (SLC25A3), a mitochondrial phosphate carrier protein, plays an important role in negatively regulating NLRP3 inflammasome activation. We found that SLC25A3 could interact with NLRP3, overexpression of SLC25A3 and knockdown of SLC25A3 could regulate NLRP3 inflammasome activation, and the interaction of NLRP3 and SLC25A3 is significantly boosted in the mitochondria when the NLRP3 inflammasome is activated. Our detailed investigation demonstrated that the interaction between NLRP3 and SLC25A3 disrupted the interaction of NLRP3-NEK7, promoted ubiquitination of NLRP3, and negatively regulated NLRP3 inflammasome activation. Thus, these findings uncovered a new regulatory mechanism of NLRP3 inflammasome activation, which provides a new perspective for the therapy of NLRP3 inflammasome-associated inflammatory diseases.
    Keywords:  Innate immune response; Mitochondria; NLRP3 inflammasome activation; SLC25A3
    DOI:  https://doi.org/10.1016/j.jbc.2024.107233
  3. Nat Commun. 2024 Mar 29. 15(1): 2751
    Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation.
    Samuel Speaks, Matthew I McFadden, Ashley Zani, Abigail Solstad, Steve Leumi, Jack E Roettger, Adam D Kenney, Hannah Bone, Lizhi Zhang, Parker J Denz, Adrian C Eddy, Amal O Amer, Richard T Robinson, Chuanxi Cai, Jianjie Ma, Emily A Hemann, Adriana Forero, Jacob S Yount.
      Influenza virus activates cellular inflammasome pathways, which can be both beneficial and detrimental to infection outcomes. Here, we investigate the function of the inflammasome-activated, pore-forming protein gasdermin D (GSDMD) during infection. Ablation of GSDMD in knockout (KO) mice (Gsdmd-/-) significantly attenuates influenza virus-induced weight loss, lung dysfunction, lung histopathology, and mortality compared with wild type (WT) mice, despite similar viral loads. Infected Gsdmd-/- mice exhibit decreased inflammatory gene signatures shown by lung transcriptomics. Among these, diminished neutrophil gene activation signatures are corroborated by decreased detection of neutrophil elastase and myeloperoxidase in KO mouse lungs. Indeed, directly infected neutrophils are observed in vivo and infection of neutrophils in vitro induces release of DNA and tissue-damaging enzymes that is largely dependent on GSDMD. Neutrophil depletion in infected WT mice recapitulates the reductions in mortality, lung inflammation, and lung dysfunction observed in Gsdmd-/- animals, while depletion does not have additive protective effects in Gsdmd-/- mice. These findings implicate a function for GSDMD in promoting lung neutrophil responses that amplify influenza virus-induced inflammation and pathogenesis. Targeting the GSDMD/neutrophil axis may provide a therapeutic avenue for treating severe influenza.
    DOI:  https://doi.org/10.1038/s41467-024-47067-0
  4. Cell Rep. 2024 Mar 22. pii: S2211-1247(24)00309-7. [Epub ahead of print]43(4): 113981
    A stress sensor, IRE1α, is required for bacterial-exotoxin-induced interleukin-1β production in tissue-resident macrophages.
    Izumi Sasaki, Yuri Fukuda-Ohta, Chihiro Nakai, Naoko Wakaki-Nishiyama, Chizuyo Okamoto, Daisuke Okuzaki, Shuhei Morita, Shiori Kaji, Yuki Furuta, Hiroaki Hemmi, Takashi Kato, Asumi Yamamoto, Emi Tosuji, Shin-Ichiroh Saitoh, Takashi Tanaka, Katsuaki Hoshino, Shinji Fukuda, Kensuke Miyake, Etsushi Kuroda, Ken J Ishii, Takao Iwawaki, Koichi Furukawa, Tsuneyasu Kaisho.
      Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1β (IL-1β), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarify the roles of inositol-requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1β production in RPMs. In RPMs, CTB is incorporated into the ER and induces ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1α-deficient RPMs show a significant impairment of CT- or CTB-induced IL-1β production, indicating that IRE1α is required for CT- or CTB-induced IL-1β production in RPMs. This study demonstrates the critical roles of IRE1α in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages.
    Keywords:  CP: Cell biology; CP: Immunology; IL-1β; IRE1α; Pyrin inflammasome; resident peritoneal macrophages
    DOI:  https://doi.org/10.1016/j.celrep.2024.113981
  5. Am J Pathol. 2024 Mar 26. pii: S0002-9440(24)00116-0. [Epub ahead of print]
    GLUT1 promotes NLRP3 inflammasome activation of airway epithelium in lipopolysaccharide-induced acute lung injury.
    Jiehong Li, Yijian Li, Guanjin Chen, Yan Liang, Jianpeng Xie, Shuiying Zhang, Kai Zhong, Tong Jiang, Haisu Yi, Haixiong Tang, Xin Chen.
      Acute lung injury (ALI) is a devastating clinical disease caused by different factors, with high morbidity and mortality. It has been shown that lung injury and inflammation caused by lipopolysaccharide (LPS) can be modulated by NLRP3 inflammasome activation, yet its exact function within the airway epithelium is still unknown. Meanwhile, glucose transporter protein 1 (GLUT1) has been shown to contribute to a number of inflammatory illnesses, including ALI. The present study was aimed to assess GLUT1's function in NLRP3 inflammasome activation of airway epithelium in LPS-induced acute lung injury. BALB/c mice (5 mg/kg) and BEAS-2B cells (200 μg/mL) were respectively exposed to LPS, with or without GLUT1 antagonists (WZB117 or BAY876). LPS upregulated pulmonary expression of NLRP3 and GLUT1 in mice, which could be blocked by WZB117 or BAY876. Pharmacological inhibition of GLUT1 in vivo significantly attenuated lung tissue damage, neutrophil accumulation, and proinflammatory factors release (TNF-α, IL-6, and IL-1β) in LPS-exposed mice. Meanwhile, the activation markers of NLRP3 inflammasome (ASC, caspase-1, IL-1β, and IL-18) induced by LPS were also suppressed. In cultured BEAS-2B cells, LPS induced an increase in GLUT1 expression and triggers activation of the NLRP3 inflammasome, both of which were inhibited by GLUT1 antagonists. These results illustrated that GLUT1 participates in LPS-induced ALI, and promotes the activation of the NLRP3 inflammasome in airway epithelial cells.
    Keywords:  Acute lung injury; GLUT1; IL-1β; NLRP3 inflammasome; epithelium
    DOI:  https://doi.org/10.1016/j.ajpath.2024.03.003
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