bims-inflin 2025-03-02 papers

Cell Rep. 2025 Feb 25. pii: S2211-1247(25)00004-X. [Epub ahead of print]44(2): 115233

Gasdermin D mediates a fast transient release of ATP after NLRP3 inflammasome activation before ninjurin 1-induced lytic cell death.

Julieta Schachter, Adriana Guijarro, Diego Angosto-Bazarra, Miriam Pinilla, Laura Hurtado-Navarro, Etienne Meunier, Ana B Pérez-Oliva, Pablo J Schwarzbaum, Pablo Pelegrin.

Pyroptosis is a lytic cell death triggered by the cleavage of gasdermin (GSDM) proteins and subsequent pore formation by the N-terminal domain oligomerization in the plasma membrane. GSDMD is cleaved by caspase-1/-4/-5/-11 upon inflammasome activation and mediates interleukin (IL)-1β and IL-18 release. GSDMD pores favor ninjurin 1 (NINJ1)-induced plasma membrane rupture and cell death. Here, we demonstrate that GSDMD mediates early ATP release upon NLRP3 inflammasome activation independently of NINJ1, occurring before IL-1β release and cell death and constituting an early danger signal. The release of ATP is a transient signal terminated before the cells continue to permeabilize and die. The different N termini of GSDMA to -E are also able to release ATP and induce monocyte migration toward pyroptotic cells. This study reveals ATP release as an early and transient danger signal depending on GSDMD plasma membrane permeabilization, independently of the late stages of lytic cell death.

Keywords: CP: Immunology; caspase-1; danger signal; extracellular nucleotide; inflammation; macrophage; nigericin; ninjurin 1; purinergic singaling; pyroptosis

DOI: https://doi.org/10.1016/j.celrep.2025.115233

Sci Rep. 2025 Feb 25. 15(1): 6713

LncRNA-Gm17586 inhibits S.typhimurium mediated pyroptosis by promoting NLRP3 and Tnip1 binding.

Zhiyuan An, Wenyi Ding.

The aim of this study is to identify the lncRNA that directly interacts with NLRP3 molecules in RAW264.7 cells infected with S. typhimurium and its role in S. typhimurium-mediated pyroptosis. We have identified LncRNA-Gm17586, which directly interacts with NLRP3 in RAW264.7 cells infected with S. typhimurium. LncRNA-Gm17586 inhibits S. typhimurium-mediated pyroptosis in RAW264.7 cells. Overexpression of LncRNA-Gm17586 not only directly suppresses NLRP3 inflammasome activation but also enhances the binding affinity between Tnip1 and NLRP3, thereby indirectly facilitating Tnip1-mediated inhibition of the NLRP3 inflammasome. Consequently, this dual mechanism effectively inhibits S. typhimurium-induced pyroptosis. Our results demonstrate that LncRNA-Gm17586 directly interacts with NLRP3 during S. typhimurium-mediated pyroptosis and inhibits this process by enhancing the interaction between Tnip1 and NLRP3.

Keywords: S.typhimurium ; LncRNA-Gm17586; Pyroptosis; RIP-seq; Tnip1

DOI: https://doi.org/10.1038/s41598-025-91296-2

Elife. 2025 Feb 25. pii: RP99939. [Epub ahead of print]13

A VgrG2b fragment cleaved by caspase-11/4 promotes Pseudomonas aeruginosa infection through suppressing the NLRP3 inflammasome.

Yan Qian, Qiannv Liu, Xiangyun Cheng, Chunlei Wang, Chun Kong, Mengqian Li, Chao Ren, Dong Jiang, Shuo Wang, Pengyan Xia.

The T6SS of Pseudomonas aeruginosa plays an essential role in the establishment of chronic infections. Inflammasome-mediated inflammatory cytokines are crucial for host defense against bacterial infections. We found that P. aeruginosa infection activates the non-canonical inflammasome in macrophages, yet it inhibits the downstream activation of the NLRP3 inflammasome. The VgrG2b of P. aeruginosa is recognized and cleaved by caspase-11, generating a free C-terminal fragment. The VgrG2b C-terminus can bind to NLRP3, inhibiting the activation of the NLRP3 inflammasome by rejecting NEK7 binding to NLRP3. Administration of a specific peptide that inhibits caspase-11 cleavage of VgrG2b significantly improves mouse survival during infection. Our discovery elucidates a mechanism by which P. aeruginosa inhibits host immune response, providing a new approach for the future clinical treatment of P. aeruginosa infections.

Keywords: NLRP3; P. aeruginosa; VgrG2b; caspase-11/4; human; immunology; inflammation; mouse; non-canonical inflammasome

DOI: https://doi.org/10.7554/eLife.99939

Cell Death Differ. 2025 Feb 28.

IL-1β drives SARS-CoV-2-induced disease independently of the inflammasome and pyroptosis signalling.

Stefanie M Bader, Lena Scherer, Jan Schaefer, James P Cooney, Liana Mackiewicz, Merle Dayton, Smitha Rose Georgy, Kathryn C Davidson, Cody C Allison, Marco J Herold, Andreas Strasser, Marc Pellegrini, Marcel Doerflinger.

Excessive inflammation and cytokine release are hallmarks of severe COVID-19. Certain programmed cell death processes can drive inflammation, however, their role in the pathogenesis of severe COVID-19 is unclear. Pyroptosis is a pro-inflammatory form of regulated cell death initiated by inflammasomes and executed by the pore-forming protein gasdermin D (GSDMD). Using an established mouse adapted SARS-CoV-2 virus and a panel of gene-targeted mice we found that deletion of the inflammasome (NLRP1/3 and the adaptor ASC) and pore forming proteins involved in pyroptosis (GSDMA/C/D/E) only marginally reduced IL-1β levels and did not impact disease outcome or viral loads. Furthermore, we found that SARS-CoV-2 infection did not trigger GSDMD activation in mouse lungs. Finally, we did not observe any difference between WT animals and mice with compound deficiencies in the pro-inflammatory initiator caspases (C1/11/12-/-). This indicates that the classical canonical and non-canonical pro-inflammatory caspases known to process and activate pro-IL-1β, pro-IL-18 and GSDMD do not substantially contribute to SARS-CoV-2 pathogenesis. However, the loss of IL-1β, but not the absence of IL-18, ameliorated disease and enhanced survival in SARS-CoV-2 infected animals compared to wildtype mice. Collectively, these findings demonstrate that IL-1β is an important factor contributing to severe SARS-CoV-2 disease, but its release was largely independent of inflammasome and pyroptotic pathways.

DOI: https://doi.org/10.1038/s41418-025-01459-x