bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–12–07
eleven papers selected by
Kateryna Shkarina, Universität Bonn
  1. Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.
  2. APIP regulates the priming of canonical NLRP3 and non-canonical Caspase-11/4 inflammasomes by binding to TRAF6.
  3. The landscape of regulated cell death: It's all downhill from here.
  4. Pharmacological inhibition of host pathways enhances macrophage killing of intracellular bacterial pathogens.
  5. ADAR1 editing is necessary for only a small subset of cytosolic dsRNAs to evade MDA5-mediated autoimmunity.
  6. SpeckSeq enables high-throughput functional stratification of MEFV variants in autoinflammatory diseases.
  7. Macrophages rescue cells from ferroptotic death.
  8. A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.
  9. Interleukin-1/Toll-like receptor signaling potentiates macrophage olfactory receptor 2-driven atherosclerosis.
  10. Apoptosis-resistant cells drive compensatory proliferation via cell-autonomous and non-autonomous functions of the initiator caspase Dronc.
  11. Platelet-mediated activation of perivascular mast cells triggers progression of sepsis to septic shock in mice.
  1. Cell. 2025 Nov 28. pii: S0092-8674(25)01251-6. [Epub ahead of print]
    Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.
    Yaqiu Wang, Jianlin Lu, Alexandre F Carisey, Sangappa B Chadchan, Ha Won Lee, R K Subbarao Malireddi, Bhesh Raj Sharma, Nagakannan Pandian, Rebecca E Tweedell, Gustavo Palacios, Nathalie Becerra Mora, Camenzind G Robinson, Aaron Pitre, Peter Vogel, Taosheng Chen, Michael P Murphy, Thirumala-Devi Kanneganti.
      The combination of innate immune activation and metabolic disruption plays critical roles in many diseases, often leading to mitochondrial dysfunction and oxidative stress that drive pathogenesis. However, mechanistic regulation under these conditions remains poorly defined. Here, we report a distinct lytic cell death mechanism induced by innate immune signaling and metabolic disruption, independent of caspase activity and previously described pyroptosis, PANoptosis, necroptosis, ferroptosis, and oxeiptosis. Instead, mitochondria undergoing BAX/BAK1/BID-dependent oxidative stress maintained prolonged plasma membrane contact, leading to local oxidative damage, a process we termed mitoxyperiosis. This process then caused membrane lysis and cell death, termed mitoxyperilysis. mTORC2 regulated the cell death, and mTOR inhibition restored cytoskeletal activity for lamellipodia to retract and mobilize mitochondria away from the membrane, preserving integrity. Activating this pathway in vivo regressed tumors in an mTORC2-dependent manner. Overall, our results identify a lytic cell death modality in response to the synergism of innate immune signaling and metabolic disruption.
    Keywords:  carbon starvation; cytokine; inflammasome; inflammatory cell death; innate immunity; mTOR; metabolism; mitochondria; oxidative damage; tumor
    DOI:  https://doi.org/10.1016/j.cell.2025.11.002
  2. Nat Commun. 2025 Dec 03. 16(1): 10866
    APIP regulates the priming of canonical NLRP3 and non-canonical Caspase-11/4 inflammasomes by binding to TRAF6.
    Kwangmin Jung, Meiko Kawamura, Bitna Lim, Manabu Abe, Kenji Sakimura, Masaaki Komatsu, Yong-Keun Jung.
      Apaf-1-interacting protein (APIP) has been implicated in inflammation-related processes, including myocardial infarction and cancer progression. However, its role in systemic inflammation remains elusive. Here, we investigate the APIP-mediated regulation of inflammasome activity in mice and human macrophages. Loss of APIP in the myeloid lineage (Apip cKO mice) compromises the activation of canonical NLRP3 and non-canonical caspase-11 inflammasomes, reducing pyroptosis in bone marrow-derived macrophages (BMDM). Conversely, these inflammatory responses are enhanced in BMDMs from APIP-transgenic mice. Consistently, APIP knockdown in human macrophages inhibits the activation of NLRP3 and caspase-4 inflammasomes. Mechanistically, APIP binds to TRAF6, activating downstream NF-κB and JNK signaling and facilitating the priming of both inflammasomes. Importantly, systemic inflammation induced by LPS or bacterial infection is attenuated in Apip cKO mice but exacerbated in APIP-transgenic mice. Thus, our findings suggest that APIP is crucial in regulating both canonical and non-canonical inflammasomes, presenting a potential therapeutic target for inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-025-65893-8
  3. Mol Cell. 2025 Dec 03. pii: S1097-2765(25)00909-8. [Epub ahead of print]
    The landscape of regulated cell death: It's all downhill from here.
    Andreas Aufschnaiter, Teak-Jung Oh, Andrew Oberst.
      Cells can die via any of several forms of regulated cell death (RCD), including apoptosis, pyroptosis, and necroptosis. We now appreciate that there is substantial crosstalk between them, allowing for a high degree of plasticity downstream of cell death triggers. Understanding this is essential to delineate roles of RCD in development, homeostasis, tumor biology, and immunity; however, this crosstalk can make the fate of individual cells difficult to visualize. Here, we present a conceptual framework that builds on Waddington's landscape model of lineage commitment. On the landscape of RCD, live cells begin atop a "mountain," from which they roll down via "valleys" representing different cell death programs, potentially being diverted or even raised back to the summit by regulators of these processes. While acknowledging that, like any conceptual framework, this visualization is imperfect, we hope it presents a succinct approach to understand the complexities and interconnections of cell death regulation.
    Keywords:  apoptosis; necroptosis; programmed cell death; pyroptosis; regulated cell death
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.013
  4. Microbiol Spectr. 2025 Dec 03. e0216325
    Pharmacological inhibition of host pathways enhances macrophage killing of intracellular bacterial pathogens.
    Ramesh Rijal, Richard H Gomer.
      After ingestion into macrophage phagosomes, some bacterial pathogens such as Mycobacterium tuberculosis (Mtb) evade killing by preventing phagosome acidification and fusion of the phagosome with a lysosome. Mtb accumulates extracellular polyphosphate (polyP), and polyP inhibits macrophage phagosome acidification and bacterial killing. In Dictyostelium discoideum, polyP also inhibits bacterial killing, and we identified some proteins in D. discoideum that polyP requires to suppress the killing of ingested bacteria. Here, we find that pharmacological inhibition of human orthologues of the D. discoideum proteins, including P2Y1 receptors, mammalian target of rapamycin, and inositol hexakisphosphate kinase, enhances the killing of Mtb, Legionella pneumophila, and Listeria monocytogenes by human macrophages. Mtb inhibits phagosome acidification, expression of the proinflammatory marker CD54, and autophagy and increases expression of the anti-inflammatory marker CD206. In Mtb-infected macrophages, the polyP-degrading enzyme polyphosphatase (ScPPX) and inhibitors reversed these effects, with ScPPX increasing CD54 expression more in female macrophages compared to male macrophages. In addition, Mtb inhibits proteasome activity, and some, but not all, inhibitors reversed these effects. While the existence of a dedicated polyP signaling pathway remains uncertain, our findings suggest that pharmacological inhibition of select host proteins can restore macrophage function and enhances the killing of intracellular pathogens.
    IMPORTANCE: Human macrophages engulf bacteria into phagosomes, which then fuse with lysosomes to kill the bacteria. However, after engulfment, pathogenic bacteria such as Mycobacterium tuberculosis, Legionella pneumophila, and Listeria monocytogenes can block phagosome-lysosome fusion, allowing their survival. Here, we show that pharmacological inhibition of specific macrophage proteins reverses these effects and enhances bacterial killing. These findings suggest that targeting host factors involved in these processes may provide a therapeutic strategy to improve macrophage function against infections such as tuberculosis, Legionnaires' disease, and listeriosis.
    Keywords:  host-directed therapies; host-pathogen interactions; intracellular pathogens; macrophage signaling pathways; polyphosphate signaling
    DOI:  https://doi.org/10.1128/spectrum.02163-25
  5. Nat Genet. 2025 Dec 03.
    ADAR1 editing is necessary for only a small subset of cytosolic dsRNAs to evade MDA5-mediated autoimmunity.
    Tao Sun, Qin Li, Jonathan M Geisinger, Shi-Bin Hu, Boming Fan, Shichen Su, Waitang Tsui, Hongchao Guo, Jinbiao Ma, Jin Billy Li.
      Endogenous long double-stranded RNAs (dsRNAs), which are not edited by the RNA editing enzyme ADAR1, may activate the antiviral dsRNA receptor MDA5 to trigger interferon-mediated immune responses. Among the large number of endogenous long dsRNAs, the key substrates that activate MDA5-termed as immunogenic dsRNAs-remain largely unidentified. Here we reveal that human immunogenic dsRNAs constitute a surprisingly small fraction of all cellular dsRNAs. We found that these immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, consistent with their role as cytosolic MDA5 substrates. We validated the MDA5-dependent immunogenicity of these dsRNAs, which was dampened following ADAR1-mediated RNA editing. Notably, immunogenic dsRNAs were enriched at genetic susceptibility loci associated with common inflammatory diseases, implying their functional importance. We anticipate that a focused analysis of immunogenic dsRNAs will enhance our understanding and treatment of cancer and inflammatory diseases, where the roles of dsRNA editing and sensing are increasingly recognized.
    DOI:  https://doi.org/10.1038/s41588-025-02430-9
  6. J Exp Med. 2026 Feb 02. pii: e20251065. [Epub ahead of print]223(2):
    SpeckSeq enables high-throughput functional stratification of MEFV variants in autoinflammatory diseases.
    Pauline Bronnec, Sarah Dalmon, Chloe Briand, Omran Allatif, Martin Broly, Melissa Marcotte, Gianluca Lombardi, Kevin Barthes, Nora Martel, Sandrine Hughes, Benjamin Gillet, Florian Milhavet, Aysima Atilgan, Hervé Bachelez, Serena Palmeri, Ignazia Prigione, Marine Madrange, Léa Savey, Michel Moutschen, Isabelle Jeru, Majdouline El Moussaoui, Alexandre Belot, Emilie Sbidian, Alessandra Carbone, Yvan Jamilloux, Marco Gattorno, Asma Smahi, Sophie Georgin-Lavialle, Guilaine Boursier, Flora Magnotti, Thomas Henry.
      Variants of uncertain significance (VUS) are a major obstacle in genetic diagnosis, particularly when involving gain-of-function (GoF) mutations that are poorly predicted in silico. MEFV, which encodes the inflammasome sensor pyrin, is mutated in two autoinflammatory diseases, familial Mediterranean fever (FMF) and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Here, we developed SpeckSeq, a method that combines DNA bar-coding, ASC speck-based single-cell sorting and next-generation sequencing to systematically identify hypermorphic MEFV variants in response to different stimuli. SpeckSeq identified 49 GoF mutations separated into two distinct groups containing either PAAND variants or FMF variants. SpeckSeq was validated using patients' cells and supported a reclassification of MEFV variant pathogenicity, leading to novel diagnoses. As a large-scale mutagenesis approach, using human genetics as a guide, SpeckSeq revealed structural and functional pyrin features, including a putative ligand-accommodating cavity in the B30.2 domain. Altogether, SpeckSeq classifies VUS to refine molecular diagnostics and improve our knowledge on the pyrin inflammasome.
    DOI:  https://doi.org/10.1084/jem.20251065
  7. Cell Death Dis. 2025 Dec 01.
    Macrophages rescue cells from ferroptotic death.
    Ruth Hefetz, Sapir Harush, Lucy Ghantous, Yael Volman, Yoel Sadovsky, Ofer Beharier, Jacob Rachmilewitz.
      Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation, has a key role in organ injury, degenerative disease, and vulnerability of therapy-resistant cancers. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we demonstrate that macrophages co-cultured with ferroptotic cancer cells from various types effectively mitigate cell death induced by GPX4 inhibitors (RSL3 and ML162), GPX4 silencing via shRNA, or the Xc- system inhibitor IKE. Furthermore, macrophages effectively reduced lipid peroxidation in ferroptotic cells. Importantly, macrophage function relies on direct cell-to-cell contact and is affected by their differentiation. Specifically, polarization into M1 macrophages, but not M2, greatly hinders their protective capabilities. Interestingly, unlike apoptotic cells, ferroptotic cells retain elevated levels of the 'don't eat me' signal, CD47, and conversely, fail to present the "eat me" signal phosphatidylserine (PS) on the outer layer of the plasma membrane, providing an opportunity for their rescue. Furthermore, in placental villi explants, macrophages protect trophoblasts from ferroptotic death. These results underscore the intricate interplay between ferroptotic cells and their microenvironment and provide compelling evidence of a yet-unrecognized anti-ferroptotic activity of macrophages as a cell-extrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.
    DOI:  https://doi.org/10.1038/s41419-025-08277-6
  8. Cell. 2025 Dec 04. pii: S0092-8674(25)01310-8. [Epub ahead of print]
    A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.
    Svenja M Lorenz, Adam Wahida, Mark J Bostock, Tobias Seibt, André Santos Dias Mourão, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S Woo, Jana K Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Cheng, Toshitaka Nakamura, Junya Ito, Sebastian Doll, Bettina Proneth, Erika Bürkle, Francesca Rizzollo, Abril Escamilla Ayala, Valeria Napolitano, Marta Kolonko-Adamska, Stefan Gaussmann, Juliane Merl-Pham, Stefanie Hauck, Anna Pertek, Tanja Orschmann, Emily van San, Tom Vanden Berghe, Daniela Hass, Adriano Maida, Joris M Frenz, Lohans Pedrera, Amalia Dolga, Markus Kraiger, Martin Hrabé de Angelis, Helmut Fuchs, Gregor Ebert, Jerica Lenberg, Jennifer Friedman, Carolin Scale, Patrizia Agostinis, Annemarie Zimprich, Daniela Vogt-Weisenhorn, Lillian Garrett, Sabine M Hölter, Wolfgang Wurst, Enrico Glaab, Jan Lewerenz, Bastian Popper, Christian Sieben, Petra Steinacker, Hans Zischka, Ana J Garcia-Saez, Anna Tietze, Sanath Kumar Ramesh, Scott Ayton, Michelle Vincendeau, Manuel A Friese, Kristen Wigby, Michael Sattler, Matthias Mann, Irina Ingold, Ashok Kumar Jayavelu, Grzegorz M Popowicz, Marcus Conrad.
      Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer's-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.
    Keywords:  Alzheimer’s disease; GPX4; SSMD; Sedaghatian type; cell death; ferroptosis; neurodegeneration; neuroinflammation; spondylometaphyseal dysplasia
    DOI:  https://doi.org/10.1016/j.cell.2025.11.014
  9. Cell Rep. 2025 Dec 03. pii: S2211-1247(25)01411-1. [Epub ahead of print]44(12): 116639
    Interleukin-1/Toll-like receptor signaling potentiates macrophage olfactory receptor 2-driven atherosclerosis.
    Lujun Zhang, Jili Fu, Zicheng Hu, Yunli Zhao, Yu Cao, Mengyu Yao, Fan Liu, Jianlin Du, Haitao Ran, Zhigang Wang, Yongyong Li, Liwen Liang, Wenhua Su, Narayan D Melgiri, Dongfang Liu, Lihong Jiang, Tianyang Hu, Rongzhong Huang, Yang Sun.
      Olfactory receptor 6A2 (OR6A2) signaling stimulates atherogenic NLRP3 inflammasome activation in vascular macrophages (Mϕs). Current evidence suggests that interleukin-1 receptor type 1 (IL-1R1)/Toll-like receptor (TLR) signaling may modulate this OR6A2-mediated inflammasome response. However, the role of and mechanism(s) by which IL-1R1/TLR signaling modulates the inflammasome response and resultant atherosclerosis remain unknown. We discovered that the interaction between β-arrestin-2 (βarr2) and OR6A2's intracellular loop 3 (OR6A2ICL3) mediates OR6A2 endocytosis, thereby inhibiting OR6A2-mediated Mϕ inflammasome activation. IL-1R1/TLR signaling promotes coupling of the coiled-coil domain of tumor necrosis factor receptor-associated factor 6 (TRAF6CCD) with βarr2, thereby blocking OR6A2ICL3-βarr2 binding, inhibiting βarr2/AP2-mediated OR6A2 internalization, and potentiating Mϕ inflammasome activation. Consistently, blocking TRAF6CCD-βarr2 coupling in vascular Mϕs inhibits octanal-induced atherosclerosis in high-cholesterol-diet-fed Ldlr-/- mice. Additionally, IL-1R1/TLR-activated βarr2K295 deSUMOylation drives TRAF6CCD-βarr2 coupling in Mϕs, and βarr2K295 deSUMOylation in vascular Mϕs promotes OR6A2-mediated atherosclerosis in high-cholesterol-diet-fed Ldlr-/- mice. In conclusion, IL-1R1/TLR-induced TRAF6CCD-βarr2 coupling, by inhibiting βarr2/AP2-mediated OR6A2 endocytosis, promotes atherogenic OR6A2-mediated NLRP3 inflammasome activation in vascular Mϕs.
    Keywords:  CP: immunology; CP: metabolism; IL-1R; OR6A2; TLR; TRAF6; atherosclerosis; inflammasome; inflammation; macrophage; β-arrestin-2
    DOI:  https://doi.org/10.1016/j.celrep.2025.116639
  10. Nat Commun. 2025 Dec 04. 16(1): 10871
    Apoptosis-resistant cells drive compensatory proliferation via cell-autonomous and non-autonomous functions of the initiator caspase Dronc.
    Tslil Braun, Naama Afgin, Lena Sapozhnikov, Ehud Sivan, Andreas Bergmann, Luis Alberto Baena-Lopez, Keren Yacobi-Sharon, Eli Arama.
      Caspases are best known for promoting apoptosis, yet their role in tissue regeneration by compensatory proliferation remains unclear. Using Drosophila wing discs and a delayed reporter for the initiator caspase-9 ortholog Dronc activity, we identify two apoptosis-resistant epithelial cell populations that mediate regeneration after ionizing radiation: Dronc-activating (DARE) and non-activating (NARE) cells. Dronc activity in DARE cells, independent of Dark and effector caspases, drives regeneration both cell-autonomously and non-cell-autonomously. The TNFR in DARE cells, Wengen, likely activated by ROS, strongly promotes DARE proliferation, while TNF/Eiger and TNFR Grindelwald moderately suppress it. Downstream, p38 MAPK is the main signaling essential for DARE and NARE cell proliferation. Myo1D ensures DARE survival by preventing lethal effector caspase activation, whereas Myo7A/Crinkled supports moderate caspase activity. Dying cells trigger DARE induction, and both DARE and NARE transmit apoptosis resistance to progeny, with DARE progeny showing enhanced resistance. Maintaining balanced DARE-NARE proliferation is crucial for proper regeneration, growth, and differentiation, insights that may be relevant to radiation-resistant cells in cancer therapy.
    DOI:  https://doi.org/10.1038/s41467-025-65996-2
  11. Nat Commun. 2025 Dec 03.
    Platelet-mediated activation of perivascular mast cells triggers progression of sepsis to septic shock in mice.
    Hae Woong Choi, Joo Hwan Noh, Jason Iskarpatyoti, Xiaoyi Zhu, Chunjing Bao, Mathew Abraham, Ulrike Hoffmann, Jamie R Privratsky, Robert H Lee, Wolfgang Bergmeier, Ephraim L Tsalik, Cassandra Fiorino, Junjie Yao, Soman N Abraham, Jörn Karhausen.
      The critical events that trigger sepsis progression into life-threatening septic shock remain unclear. In agreement with reports that link a drop in platelet count to a complicated clinical course in sepsis patients, here we report that, during sepsis, mouse platelets become activated, deposit systemically on vascular walls, and stimulate perivascular mast cells (MC) by releasing platelet activating factor (PAF). In mouse models and patient samples, MC activation correlates with the development of shock in sepsis and is mechanistically linked to shock by inducing systemic hypotension, vascular leakage and microvascular perfusion abnormalities. Preventing platelet or MC activation, or inhibiting the activity of the major MC granule constituent chymase, averts progression from sepsis to shock and reduces mortality of septic mice. Thus, our work establishes that, during sepsis progression, platelet microvascular adhesion leads to MC-mediated vascular changes to culminate in septic shock and septic shock-associated mortality.
    DOI:  https://doi.org/10.1038/s41467-025-66978-0
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