bims-inflin Biomed News
on Inflammasome and infection
Issue of 2025–05–18
six papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto
  1. Gasdermin-D pores induce an inactivating caspase-4 cleavage that limits IL-18 production in the intestinal epithelium.
  2. rFIP-nha activates macrophages towards a pro-inflammatory phenotype via AIM2 inflammasome modulation.
  3. Caspase-1-licensed pyroptosis drives dsRNA-mediated necroptosis and dampens host defense against bacterial pneumonia.
  4. Malnutrition exacerbates pathogenesis of Lutzomyia longipalpis sand fly-transmitted Leishmania donovani.
  5. In vitro study: HIF-1α-dependent glycolysis enhances NETosis in hypoxic conditions.
  6. RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection.
  1. Commun Biol. 2025 May 13. 8(1): 737
    Gasdermin-D pores induce an inactivating caspase-4 cleavage that limits IL-18 production in the intestinal epithelium.
    J K Bruce, L Y Li, Y Tang, E G Forster, N J Winsor, P Y Bi, C Krustev, S Keely, J E Lee, J R Rohde, H Y Gaisano, D J Philpott, S E Girardin.
      Intestinal epithelial-derived IL-18 is critical for homeostatic intestinal barrier function and is secreted through Gasdermin D (GSDMD) pores. Inflammasome activation is a prerequisite for both IL-18 maturation and GSDMD pore formation. However, GSDMD pores also cause pyroptotic cell death, which could be detrimental to the intestinal epithelial barrier. How epithelial cells balance the need to secrete IL-18 and to maintain barrier integrity remains poorly understood. In human intestinal epithelial cell lines and in primary human epithelial intestinal organoids, but not in immune cells, GSDMD plasma membrane pore formation by LPS electroporation and by gram-negative bacterial infection induced a non-conventional p37 caspase-4 fragment that was associated with reduced levels of mature IL-18. By contrast, limiting GSDMD plasma membrane pores pharmacologically and via point-mutagenesis prevented caspase-4 cleavage and increased IL-18 production, suggesting that p37 caspase-4 cleavage may regulate IL-18 maturation in the intestinal epithelium. In support, co-expression of caspase-4 cleavage mutants and IL-18 in HEK293T cells revealed that non-cleavable caspase-4 produced more mature IL-18 than cleaved caspase-4. Overall, these studies suggest that epithelial inflammasomes encode feedback pathways that control the balance between cytokine secretion and cell death. This may be an important mechanism to ensure homeostatic IL-18 production in the intestinal epithelium.
    DOI:  https://doi.org/10.1038/s42003-025-08183-9
  2. Front Cell Dev Biol. 2025 ;13 1533742
    rFIP-nha activates macrophages towards a pro-inflammatory phenotype via AIM2 inflammasome modulation.
    Yusi Liu, Zhen Li, Harry Wichers, Shanna Bastiaan-Net, Tamara Hoppenbrouwers.
      Fungal immunomodulatory proteins (FIPs) are small proteins from fungi with considerable immunomodulatory activity. FIP-nha (Nectria haematococca) contains two glycosylation sites at positions N5 and N39, and displays a high thermostability and notable anti-tumour activity. However, FIP-nha's immunomodulatory activity on macrophages and the associated mechanism remain unclear. In this study, three rFIP-nha glycan mutants (N5A, N39A, N5+39A) were recombinantly expressed in Pichia pastoris. To test the impact on FIP-nha's immunomodulatory activity, the phagocytotic activity, cytokine secretion, and gene expression of THP-1 macrophages were investigated. rFIP-nha and its mutants reduced macrophage phagocytosis, and induced IL-1β, IL-12 and IL-10 cytokine secretion significantly, indicating that the protein confers a pro-inflammatory behaviour on THP-1 macrophages. However, there were no obvious differences among the different glycan mutants, indicating that the observed activation mechanisms are likely glycosylation-independent. Furthermore, to study the immunomodulatory mechanism, four kinds of inflammasomes (NLRP1, NLRP3, NLRC4 and AIM2) were tested at transcriptional level. AIM2 was found to be 10-fold upregulated. Then, THP1-KO-ASC cells and AIM2 related inhibitors showed that IL-1β release induced by rFIP-nha is ASC signalling pathway dependent. Taken together, these findings suggest that rFIP-nha activates THP-1 macrophages in a pro-inflammatory way by activating the AIM2 inflammasome.
    Keywords:  AIM2 inflammasome; IL-1β; glycosylation; immunomodulatory protein; macrophage; pro-inflammatory
    DOI:  https://doi.org/10.3389/fcell.2025.1533742
  3. PLoS Pathog. 2025 May 13. 21(5): e1013167
    Caspase-1-licensed pyroptosis drives dsRNA-mediated necroptosis and dampens host defense against bacterial pneumonia.
    Qinyu Luo, Lihua Shen, Shiyue Yang, Yan Zhang, Yihang Pan, Zehua Wu, Qiang Shu, Qixing Chen.
      Bacterial lung infections cause severe host responses. Here, we showed that global deficiency of caspase-1 can protect against lethal pulmonary Escherichia coli infection by reducing the necroptosis of infiltrated neutrophils, which are key players in immune responses in the lung. Mechanistically, neutrophil necroptosis was not directly triggered in a cell-intrinsic manner by invading bacteria but was triggered by bacteria-stimulated pyroptotic epithelial cell supernatants in vitro. In validation experiments, chimeric mice with nonhematopoietic caspase-1 or GSDMD knockout were protected from lung E. coli infection and exhibited decreased neutrophil death. Nonhematopoietic pyroptosis facilitates the release of dsRNAs and contributes to neutrophil ZBP1-related necroptosis. Moreover, blocking dsRNA or depleting ZBP1 ameliorated the pathophysiological process of pulmonary E. coli infection. Overall, our results demonstrate a paradigm of communication between necroptosis and pyroptosis in different cell types in cooperation with microbes and hosts and suggest that therapeutic targeting of the pyroptosis or necroptosis pathway may prevent pulmonary bacterial infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1013167
  4. Commun Biol. 2025 May 13. 8(1): 746
    Malnutrition exacerbates pathogenesis of Lutzomyia longipalpis sand fly-transmitted Leishmania donovani.
    Eva Iniguez, Johannes Doehl, Pedro Cecilio, Tiago Donatelli Serafim, Caroline Percopo, Yvonne Rangel-Gonzalez, Somaditya Dey, Elvia J Osorio, Patrick Huffcutt, Sofia Roitman, Claudio Meneses, Mara Short, Jesus G Valenzuela, Peter C Melby, Shaden Kamhawi.
      Visceral leishmaniasis (VL) is transmitted by Leishmania-infected sand fly bites and malnutrition is a known risk factor in human VL. Models using sand fly transmission or malnutrition promote parasite dissemination. By investigating features of L. donovani-Lutzomyia longipalpis transmission to malnourished mice, we show that a comparable IL1-β-driven acute inflammation is maintained in malnourished (MN-SF) and well-nourished (WN-SF) sand fly-infected mice. However, parasite dissemination was more pronounced in MN-SF that had a significantly higher acute (P ≤ 0.001) and chronic (P ≤ 0.0001) splenic parasite burden compared to WN-SF. Compared to WN-SF, MN-SF exhibited chronic clinical symptoms (P ≤ 0.0001), neutrophilia (P ≤ 0.001), lymphocytopenia (P ≤ 0.0001), increased heme oxygenase-1 (P ≤ 0.001) and IL17-A (P ≤ 0.0001) levels, dysregulation of liver enzymes, lymph node barrier dysfunction, and augmented dysbiosis, all associated with enhanced VL severity. Combining vector-transmission and malnutrition provides an improved model to study VL pathogenesis and host defense.
    DOI:  https://doi.org/10.1038/s42003-025-08106-8
  5. Front Immunol. 2025 ;16 1583587
    In vitro study: HIF-1α-dependent glycolysis enhances NETosis in hypoxic conditions.
    Yi Ye, Yanjun Wang, Qiying Xu, Juanli Liu, Ziqi Yang, Tana Wuren, Ri-Li Ge.
       Background: Hypoxia plays a pivotal role in modulating immune responses, especially in neutrophils, which are essential components of the innate immune system. Hypoxia-inducible factor (HIF)-1α, a key transcription factor in hypoxic adaptation, regulates cellular metabolism and inflammatory responses. However, the impact of HIF-1α-dependent glycolysis on the formation of neutrophil extracellular traps (known as NETosis) under hypoxic conditions remains unclear.
    Methods: We employed two established neutrophil models, neutrophils isolated from human whole blood and DMSO-induced dHL-60 cells, to explore the role of HIF-1α in regulating glycolysis and its influence on NETosis under hypoxic conditions. We utilized western blotting, immunofluorescence staining, ELISA, and flow cytometry to evaluate the expression of key glycolytic enzymes and NETosis markers under hypoxia. Additionally, the effects of inhibiting HIF-1α with LW6 and blocking the glycolytic pathway with Bay-876 were investigated.
    Results: HIF-1α-dependent glycolysis, through the upregulation of key glycolytic enzymes, significantly enhances NETosis under hypoxic conditions. Pharmacological inhibition of HIF-1α with LW6 and glycolytic blockade with Bay-876 markedly reduced NETosis, underscoring the crucial role of metabolic reprogramming in neutrophil function during hypoxia.
    Conclusion: This study provides novel insights into the interplay between metabolic reprogramming and NETosis in response to hypoxic stress. We identify HIF-1α-dependent glycolysis as a key driver of NETs formation, advancing our understanding of the mechanisms underlying hypoxia-related inflammatory diseases. These findings also suggest that targeting metabolic pathways may offer potential therapeutic strategies for modulating immune responses in hypoxia-associated disorders.
    Keywords:  HIF-1α; glycolysis; hypoxia; neutrophil extracellular traps; neutrophils
    DOI:  https://doi.org/10.3389/fimmu.2025.1583587
  6. Cell Death Differ. 2025 May 14.
    RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection.
    Yuanyuan Li, Wenqing Gao, Yuxin Qiu, Jiasong Pan, Qingqing Guo, Xuehe Liu, Lu Geng, Yajie Shen, Yifan Deng, Zhidong Hu, Suhua Li, Shanshan Liu, Adi Idris, Jinqing Huang, Hua Yang, Baoxue Ge, Xiaoyong Fan, Xiangjun Chen, Jixi Li.
      RING1 is an E3 ligase component of the polycomb repressive complex 1 (PRC1) with known roles in chromatin regulation and cellular processes such as apoptosis and autophagy. However, its involvement in inflammation and pyroptosis remains elusive. Here, we demonstrate that human RING1, not RING2, promotes K48-linked ubiquitination of Gasdermin D (GSDMD) and acts as a negative regulator of pyroptosis and bacterial infection. Indeed, we showed that loss of Ring1 increased S. typhimurium infectious load and mortality in vivo. Though RING1 deletion initially reduced M. tuberculosis (Mtb) infectious load in vivo, increased lung inflammation and impaired immune defense responses were later observed. Moreover, Ring1 knockout exacerbated acute sepsis induced by lipopolysaccharide (LPS) in vivo. Mechanistically, RING1 directly interacts with GSDMD and ubiquitinates the K51 and K168 sites of GSDMD for K48-linked proteasomal degradation, thereby inhibiting pyroptosis. Inhibition of RING1 E3 ligase activity by direct mutation or with the use of small molecule inhibitors increased GSDMD level and cell death during pyroptosis. Our findings reveal that RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection, highlighting RING1 as a potential therapeutic target for combating infectious diseases.
    DOI:  https://doi.org/10.1038/s41418-025-01527-2
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