bims-inflin Biomed News
on Inflammasome and infection
Issue of 2024–08–11
six papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto
  1. Pyroptosis leads to loss of centrosomal integrity in macrophages.
  2. Overexpression of NLRP12 enhances macrophage immune response and alleviates herpes simplex keratitis.
  3. FDA-approved disulfiram inhibits the NLRP3 inflammasome by regulating NLRP3 palmitoylation.
  4. Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation.
  5. Septins promote macrophage pyroptosis by regulating gasdermin D cleavage and ninjurin-1-mediated plasma membrane rupture.
  6. Lipopolysaccharide-induced bacterial infection model: microRNA-370-3p participates in the anti-infection response by targeting the macrophage TLR4-NLRP3 caspase-1 cellular pyroptosis pathway.
  1. Cell Death Discov. 2024 Aug 08. 10(1): 354
    Pyroptosis leads to loss of centrosomal integrity in macrophages.
    Siyi Bai, Fatima Martin-Sanchez, David Brough, Gloria Lopez-Castejon.
      NLRP3 forms a multiprotein inflammasome complex to initiate the inflammatory response when macrophages sense infection or tissue damage, which leads to caspase-1 activation, maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and Gasdermin-D (GSDMD) mediated pyroptosis. NLRP3 inflammasome activity must be controlled as unregulated and chronic inflammation underlies inflammatory and autoimmune diseases. Several findings uncovered that NLRP3 inflammasome activity is under the regulation of centrosome localized proteins such as NEK7 and HDAC6, however, whether the centrosome composition or structure is altered during the inflammasome activation is not known. Our data show that levels of the centrosomal scaffold protein pericentrin (PCNT) are reduced upon NLRP3 inflammasome activation via different activators in human and murine macrophages. PCNT loss occurs in the presence of membrane stabilizer punicalagin, suggesting this is not a consequence of membrane rupture. We found that PCNT loss is dependent on NLRP3 and active caspases as MCC950 and pan caspase inhibitor ZVAD prevent its degradation. Moreover, caspase-1 and GSDMD are both required for this NLRP3-mediated PCNT loss because absence of caspase-1 or GSDMD triggers an alternative regulation of PCNT via its cleavage by caspase-3 in response to nigericin stimulation. PCNT degradation occurs in response to nigericin, but also other NLRP3 activators including lysomotropic agent L-Leucyl-L-Leucine methyl ester (LLOMe) and hypotonicity but not AIM2 activation. Our work reveals that the NLRP3 inflammasome activation alters centrosome composition highlighting the need to further understand the role of this organelle during inflammatory responses.
    DOI:  https://doi.org/10.1038/s41420-024-02093-1
  2. Front Cell Infect Microbiol. 2024 ;14 1416105
    Overexpression of NLRP12 enhances macrophage immune response and alleviates herpes simplex keratitis.
    Jiaxuan Jiang, Di Zhang, Wei Liu, Jingya Yang, Fan Yang, Junpeng Liu, Kai Hu.
       Introduction: Herpes simplex keratitis (HSK) is a blinding disease caused by corneal infection of Herpes simplex virus type 1 (HSV-1). Effective clearance of HSV-1 from the infected cornea is crucial for HSK management. Macrophages play an important part in the innate immune defense against viral infections. This study investigates the immunomodulatory role of NLRP12 in macrophage immune response during HSV-1 infection.
    Methods: NLRP12 expression post-infection was assessed in various macrophage cell lines. Overexpression of NLRP12 was achieved by lentiviral transfection, and its effect on HSV-1 replication and immune responses were examined. Mechanistic insights into the role of NLRP12 were explored using immunofluorescence and Western Blot. For in vivo studies, ocular adoptive transfer of NLRP12-overexpressing bone marrow derived macrophages (BMDMs) was performed. HSV-1 viral loads, HSK symptoms, and macrophage-mediated immune responses were investigated.
    Results: A significant decrease in NLRP12 expression post-infection was observed in various macrophage cell lines. Overexpression of NLRP12 in macrophages reduced HSV-1 replication. Mechanistically, overexpression of NLRP12 triggered early and robust pyroptosis in response to HSV-1 infection, inducing interleukin (IL)-18 production and activating downstream antiviral responses through the JAK-STAT signaling pathway. In vivo, ocular adoptive transfer of NLRP12-overexpressing BMDMs to mouse corneas alleviated HSK damage and reduced HSV-1 viral loads. NLRP12-overexpressing BMDMs improved antiviral responses in the cornea and promoted the maturation of corneal-infiltrating macrophages and dendritic cells. Additionally, NLRP12-overexpressing BMDMs amplified the adaptive immune response in the submandibular draining lymph nodes.
    Discussion: These findings highlight the role of NLRP12 in macrophage-mediated immune response against HSV-1 infection and suggest its potential for possible immunotherapy for HSK.
    Keywords:  NLRP12; antiviral; herpes simplex keratitis; herpes simplex virus type 1; macrophage; pyroptosis
    DOI:  https://doi.org/10.3389/fcimb.2024.1416105
  3. Cell Rep. 2024 Aug 07. pii: S2211-1247(24)00959-8. [Epub ahead of print]43(8): 114609
    FDA-approved disulfiram inhibits the NLRP3 inflammasome by regulating NLRP3 palmitoylation.
    Jie Xu, Joseph M Pickard, Gabriel Núñez.
      The NLRP3 inflammasome is dysregulated in autoinflammatory disorders caused by inherited mutations and contributes to the pathogenesis of several chronic inflammatory diseases. In this study, we discovered that disulfiram, a safe US Food and Drug Administration (FDA)-approved drug, specifically inhibits the NLRP3 inflammasome but not the NLRC4 or AIM2 inflammasomes. Disulfiram suppresses caspase-1 activation, ASC speck formation, and pyroptosis induced by several stimuli that activate NLRP3. Mechanistically, NLRP3 is palmitoylated at cysteine 126, a modification required for its localization to the trans-Golgi network and inflammasome activation, which was inhibited by disulfiram. Administration of disulfiram to animals inhibited the NLRP3, but not NLRC4, inflammasome in vivo. Our study uncovers a mechanism by which disulfiram targets NLRP3 and provides a rationale for using a safe FDA-approved drug for the treatment of NLRP3-associated inflammatory diseases.
    Keywords:  CP: Immunology; NLRP3; disulfiram; gasdermin D; inflammasome; palmitoylation
    DOI:  https://doi.org/10.1016/j.celrep.2024.114609
  4. Nat Commun. 2024 Aug 05. 15(1): 6640
    Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation.
    Si-Jia Sun, Xiao-Dong Jiao, Zhi-Gang Chen, Qi Cao, Jia-Hui Zhu, Qi-Rui Shen, Yi Liu, Zhen Zhang, Fang-Fang Xu, Yu Shi, Jie Tong, Shen-Xi Ouyang, Jiang-Tao Fu, Yi Zhao, Jun Ren, Dong-Jie Li, Fu-Ming Shen, Pei Wang.
      Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.
    DOI:  https://doi.org/10.1038/s41467-024-50996-5
  5. Cell Chem Biol. 2024 Jul 30. pii: S2451-9456(24)00305-2. [Epub ahead of print]
    Septins promote macrophage pyroptosis by regulating gasdermin D cleavage and ninjurin-1-mediated plasma membrane rupture.
    Dominik Brokatzky, Margarida C Gomes, Stevens Robertin, Carolina Albino, Sydney L Miles, Serge Mostowy.
      The septin cytoskeleton is primarily known for roles in cell division and host defense against bacterial infection. Despite recent insights, the full breadth of roles for septins in host defense is poorly understood. In macrophages, Shigella induces pyroptosis, a pro-inflammatory form of cell death dependent upon gasdermin D (GSDMD) pores at the plasma membrane and cell surface protein ninjurin-1 (NINJ1) for membrane rupture. Here, we discover that septins promote macrophage pyroptosis induced by lipopolysaccharide (LPS)/nigericin and Shigella infection, but do not affect cytokine expression or release. We observe that septin filaments assemble at the plasma membrane, and cleavage of GSDMD is impaired in septin-depleted cells. We found that septins regulate mitochondrial dynamics and the expression of NINJ1. Using a Shigella-zebrafish infection model, we show that septin-mediated pyroptosis is an in vivo mechanism of infection control. The discovery of septins as a mediator of pyroptosis may inspire innovative anti-bacterial and anti-inflammatory treatments.
    Keywords:  NINJ1; Shigella; gasdermin D; inflammasome; macrophage; mitochondria; pyroptosis; septins; zebrafish
    DOI:  https://doi.org/10.1016/j.chembiol.2024.07.003
  6. Int J Immunopathol Pharmacol. 2024 Jan-Dec;38:38 3946320241272550
    Lipopolysaccharide-induced bacterial infection model: microRNA-370-3p participates in the anti-infection response by targeting the macrophage TLR4-NLRP3 caspase-1 cellular pyroptosis pathway.
    Wen Liu, Haiyun Chen, Fengli Xia, Lu Lu, Abdusemer Reyimu, Paerhati Pawuziye, Yadong Li, Aimin Xu, Xiaoguang Zou.
       OBJECTIVE: To explore the effect of miR-370-3p on LPS triggering, in particular its involvement in disease progression by targeting the TLR4-NLRP3-caspase-1 cellular pyroptosis pathway in macrophages.
    METHODS: Human macrophage RAW264.7 was divided into 6 groups: control, LPS, LPS + inhibitor-NC, LPS + miR-370-3p inhibitor, LPS + mimics-NC and LPS + miR-370-3p mimics. RT-qPCR was used to detect the expression level of miR-370-3p and analyzed comparatively. CCK-8 and flow cytometry assays were used to detect cell viability and apoptosis. ELISA assay was used to detect the levels of IL-1β and TNF-α in the supernatant of the cells. The WB assay was used to detect TLR4, NLRP3, Caspase-1 and GSDMD levels.
    RESULTS: After LPS induction, macrophage miR-370-3p levels decreased, cell viability decreased, and apoptosis increased. At the same time, the levels of TLR4, NLRP3, Caspase-1 and GSDMD increased in the cells, and the levels of IL-1β and TNF-α increased in the cell supernatant. Compared with the LPS group, the significantly higher expression level of miR-370-3p in the cells of the LPS + miR-370-3p mimics group was accompanied by significantly higher cell viability, significantly lower apoptosis rate, significantly lower levels of TLR4, NLRP3, Caspase-1, and GSDMD in the cells, and significantly lower levels of IL-1β and TNF-α in the cell supernatant.
    CONCLUSION: MiR-370-3p may be involved in anti-infective immune responses by targeting and inhibiting the macrophage TLR4-NLRP3-caspase-1 cellular pyroptosis pathway.
    Keywords:  TLR4-NLRP3-caspase-1; cellular pyroptosis; macrophage; miR-370-3p
    DOI:  https://doi.org/10.1177/03946320241272550
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