bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–03–08
nine papers selected by
Kateryna Shkarina, Universität Bonn
  1. Toxoplasma gondii effector MAF1 blocks mouse AIM2 inflammasome activation by inhibiting mtDNA release.
  2. Z-DNA binding protein 1 mediates necroptotic cell death in primary murine microglia following herpes simplex virus-1 infection.
  3. Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome.
  4. Exclusion of Notch from the contact site during efferocytosis restricts anticancer immunity.
  5. Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4.
  6. Lipid asymmetry disruption by XKR8 orchestrates neutrophil extracellular trap formation and inhibits fungal infection.
  7. Necroptosis in both tumour and stromal compartments determines responsiveness to immunogenic cell death-based immunotherapy.
  8. Phagocytosis of necroptotic cells optimizes type 1 conventional dendritic cells for induction of a cytotoxic T-cell response.
  9. Lipocalin 2 orchestrates resistance to ferroptosis via AXL.
  1. J Immunol. 2026 Feb 09. pii: vkaf360. [Epub ahead of print]215(2):
    Toxoplasma gondii effector MAF1 blocks mouse AIM2 inflammasome activation by inhibiting mtDNA release.
    Xiao-Yu Zhao, Nadia K Holness, Samantha L Lempke, Lena Pernas, Laura E Newman, Sarah E Ewald.
      Toxoplasma gondii is an obligate intracellular pathogen that can infect most nucleated cell types in rodents and humans. Parasite infection is regulated by inflammasome activation, downstream of Toll-like receptors (TLRs) priming, and interferon γ (IFN-γ)-mediated activation of immunity inducible GTPases. In vivo, the activation of these pathways overlaps, however, the molecular mechanism of cooperation between IFN-γ signaling and inflammasome activation has not been rigorously explored during T. gondii infection. Here we show that IFN-γ is sufficient to prime T. gondii-induced inflammasome activation in murine myeloid cells. The cytosolic DNA sensor absent in melanoma 2 (AIM2) inflammasome plays a dominant role in IL-1β release through caspase-1/11 and ASC in cooperation with NLRP3. Unexpectedly, we found that AIM2 inflammasome activation was not dependent on parasite killing as iNOS-deficiency rescued T. gondii clearance but did not inhibit IL-1β release or cell death. Instead, we found that depleting host mitochondrial DNA (mtDNA) blocked IL-1β release, suggesting that host DNA is the ligand for AIM2. Moreover, we found that expressing mitochondrial association factor 1 (MAF1I) from the hyper-virulent type I strain in type II T. gondii significantly inhibited the release of mtDNA into the host cell cytosol and reduced inflammasome activation. These data indicate that T. gondii infection in the context of IFN-γ signaling leads to AIM2 inflammasome activation by host mtDNA, a process that is competitively inhibited by MAF1I-mediated mitochondrial recruitment to the parasitophorous vacuole.
    Keywords:   Toxoplasma gondii ; inflammasome; inflammation; mtDNA
    DOI:  https://doi.org/10.1093/jimmun/vkaf360
  2. J Neurovirol. 2026 Mar 02. pii: 10. [Epub ahead of print]32(2):
    Z-DNA binding protein 1 mediates necroptotic cell death in primary murine microglia following herpes simplex virus-1 infection.
    Alexander J Suptela, Ian Marriott.
      The mechanisms by which microglia respond to viral central nervous system (CNS) pathogens are now becoming apparent with the demonstration that they express an array of pattern recognition receptors that include cytosolic sensors for exogenous nucleic acids. We have previously shown that microglia express Z-DNA binding protein 1 (ZBP1) and found that this sensor contributes to their inflammatory responses to the clinically relevant DNA virus, herpes simplex virus-1 (HSV-1). More recently, we showed that ZBP1 serves as a restriction factor for HSV-1 in murine astrocytes and is associated with the induction of both necroptotic and apoptotic cell death pathways in these cells. Here, we demonstrate that this cytosolic DNA sensor similarly functions as a HSV-1 restriction factor in primary murine microglia. However, unlike astrocytes, we have determined that a neuroinvasive clinically-derived HSV-1 isolate induces necroptosis, but not apoptosis, in these myeloid cells in a ZBP1-dependent as well as a ZBP1-independent manner. Interestingly, we found that a laboratory adapted HSV-1 strain elicits microglial apoptosis in a ZBP-1-independent manner, in addition to both ZBP1-dependent and independent necroptosis, indicating that viral strain-specific differences may exist. However, it remains to be seen whether ZBP1-mediated cell death in microglia contributes significantly to host protection or, rather, exacerbates DNA virus-associated CNS pathology in mice.
    Keywords:  Apoptosis; HSV-1; Microg; Necroptosis; ZBP-1
    DOI:  https://doi.org/10.1007/s13365-025-01304-4
  3. Sci Adv. 2026 Mar 06. 12(10): eaeb9507
    Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome.
    Martin C Moncrieffe, Prasanna Suresh, Joe Boyle, Yuhao Cui, Bharti Nawalpuri, Brett Verstak, Yu P Zhang, Ziwei Zhang, Marcus Taylor, Edward H Egelman, Nicholas Gay, David Klenerman, Clare Bryant.
      Toll-like receptors (TLRs) drive innate immunity via assembly of macromolecular signal transduction platforms [supramolecular organizing centers (SMOCs)] coordinated by adaptor proteins such as Toll/interleukin-1 receptor (IL-1R) domain-containing adaptor-inducing interferon-β (TRIF), but whether oligomeric TRIFosomes form is unknown. Here, using cryo-electron microscopy and biophysical characterization of full-length TRIF in vitro, we show that it forms filamentous oligomers, which associate with the TRIF signaling partners receptor interacting protein 1 (RIP1) and RIP3 kinases, suggesting that oligomeric TRIFosomes could form. Endogenous TRIF, however, is predominantly monomeric in the absence of ligand, only forming TRIFosome oligomers in macrophages after stimulation of TLR4 or TLR3 when large, macromolecular signaling complexes form. TRIFosomes are fully formed 45 min after TLR3 or 60 min after TLR4 stimulation, commensurate with activation of nuclear factor κB in these cells. TLR3/4 activation triggers rapid interferon signaling prior to TRIFosome formation through monomeric TRIF, unexpectedly suggesting that a macromolecular platform of TRIF is not required to drive this signaling pathway. Collectively, these data show TRIFosome macromolecular platform formation and, unexpectedly, that TLR signaling can be SMOC-independent in addition to being SMOC-dependent.
    DOI:  https://doi.org/10.1126/sciadv.aeb9507
  4. Nat Immunol. 2026 Mar 03.
    Exclusion of Notch from the contact site during efferocytosis restricts anticancer immunity.
    Zhenrui Li, Beisi Xu, Piyush Sharma, Cliff Guy, Emilio Boada-Romero, Katherine Verbist, Ao Guo, Luigi Mari, Suresh Poudel, Mao Yang, Douglas R Green.
      The clearance of dying cells by phagocytes (efferocytosis) is important for maintenance of tissue homeostasis and the active repression of inflammatory responses but can promote an immunosuppressive tumor microenvironment. Here we show that Notch signaling is suppressed actively during efferocytosis and that activation of this pathway by ectopic expression of the Notch intracellular domain in myeloid cells improves anticancer immunity in mice. Contact with dead cells or IgG-coated surfaces induces the activation of an integrin barrier that excludes Notch from the contact site to prevent it signaling. The formation of this active integrin barrier requires the Rubicon-VPS34 complex, which recruits phospholipase D (PLD) to regulate integrin activation. Ablation of Rubicon in the host or inhibition of PLD increases Notch activation during efferocytosis and improves anticancer immunity in a manner dependent on Notch signaling. These findings identify a regulatory mechanism that restricts Notch signaling during efferocytosis.
    DOI:  https://doi.org/10.1038/s41590-026-02452-3
  5. Nat Cell Biol. 2026 Mar 06.
    Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4.
    Alexis Betrancourt, M Talha Cinko, Ana Beatriz Varanda, Maykel Arias, Iratxe Uranga-Murillo, Natacha Peña, Lucia-Maria Kaps, Long Fung Chau, Bianca Buratti, Johannes Brägelmann, Diego de Miguel, Kerstin Becker, Ramona Casper, Rocio Martin, Antonio Alcami, Brian J Ferguson, Julian Pardo, Eva Rieser, Henning Walczak.
      Pattern recognition receptor (PRR)-induced interferon (IFN) is critical for effective immunity. The PRRs Toll-like receptor (TLR) 3, TLR4 and cyclic GMP-AMP synthase (cGAS), together with the stimulator of IFN genes (STING), signal through TANK-binding kinase 1 (TBK1), which activates the type-I/III IFN-inducing transcription factor interferon-response factor 3 (IRF3). The mechanism by which these PRRs activate TBK1 remains unresolved. Here we show that lysine-11 (K11)-linked ubiquitination drives TBK1 activation by these PRRs. The E3 ligase ANKIB1 attaches K11-linked ubiquitin chains to components of the TLR3- and cGAS-STING-induced signalosomes. This facilitates Optineurin recruitment to these complexes, in turn enabling recruitment and activation of TBK1 and IRF3, defining an uncharacterized signalling axis. In mice, ANKIB1 deficiency dampens IFN induction via TLR3 and cGAS-STING, reducing interferonopathy and compromising protection against HSV-1, respectively. Together, our results demonstrate an unanticipated and critical role for ANKIB1-generated K11-linked ubiquitination in the immune response activated by cGAS-STING, TLR3 and TLR4.
    DOI:  https://doi.org/10.1038/s41556-026-01886-z
  6. Nat Immunol. 2026 Mar 04.
    Lipid asymmetry disruption by XKR8 orchestrates neutrophil extracellular trap formation and inhibits fungal infection.
    Weixiang Liu, Jieming Ping, Lishan Deng, Ke Wang, Jinnuo Xu, Ningxin Peng, Mengyun Yang, Hesen Tang, Zhengjie Liu, Wenliang Wang, Tao Li, Jun Xie, Yunyun Han, Zhongjun Dong, Wei Hu, Zheng Liu, Ning Wu.
      Neutrophil extracellular traps (NETs) constitute a vital antimicrobial defense mechanism of neutrophils, contributing to various physio-pathological processes; however, the role of plasma membrane asymmetry in this process remains unknown. Here we identify Xk-related protein 8 (XKR8), a plasma membrane phospholipid scramblase, as a pivotal regulator of NETs formation. Upon NETs induction, XKR8 is cleaved by caspase-3, thereby disrupting plasma membrane lipid asymmetry via phospholipid scrambling. Mutation of the caspase-3 cleavage site in XKR8 impairs NET formation. Inhibition of calcium signals before lipid scrambling abrogates NET formation, whereas blockade after scrambling does not. Cleaved XKR8 reorients plasma membrane lipids, altering membrane lipid tension and promoting Ca2+ signals through mechanosensitive channels. XKR8-deficient mice exhibit compromised NET formation and impaired control of Candida albicans pulmonary infection, showing that XKR8 is indispensable for neutrophil-driven immune responses in vivo. These findings define caspase-3-XKR8plasma membrane phospholipid scrambling as a central mechanism controlling NET formation and underscore its critical role in neutrophil-dependent antifungal immunity.
    DOI:  https://doi.org/10.1038/s41590-026-02456-z
  7. Nat Commun. 2026 Mar 06.
    Necroptosis in both tumour and stromal compartments determines responsiveness to immunogenic cell death-based immunotherapy.
    Winnie Fernando, Jarama Clucas, Alberto Rizzo, Ramsay Singer, Emily Goode, Crescens Tiu, Scott Layzell, Joshua Konecnik, Rebecca Wilson, Sidonie Wicky John, Samuel Jouny, Naomi Guppy, Victoire Boulat, Jonathan Mannion, Maria Goicoechea, Shaun Tan, Sam Lawson, Chris Starling, Gabrielle Elshtein, Nivedita Ravindran, Anna B Montgomery, Rosa Andres-Ejarque, Mark Allen, Steven Lumbard, Fredrik Wallberg, Kai Betteridge, Ross Scrimgeour, David Robertson, George Ward, Martin Sims, Tomoko Smyth, Andre L Samson, James M Murphy, Daniela Kolarevic Ivankovic, Esther N Arwert, Dinis P Calado, Anita Grigoriadis, Matthew J Smalley, Alan Melcher, Syed Haider, Toby Lawrence, Ioannis Roxanis, Andrew N J Tutt, Tencho Tenev, Pascal Meier.
      Immunotherapy has transformed cancer treatment, including early triple-negative breast cancer (TNBC), yet most patients with advanced TNBC fail to respond to immune checkpoint blockade (ICB) plus chemotherapy. Durable control likely requires not only tumour cell killing but also immunogenic cell death (ICD) that activates antitumour immunity. Using a Brca1⁻/⁻p53⁻/⁻ organoid-derived TNBC model that recapitulates the immune landscapes of basal-like tumours, we show that RIPK1-driven ICD synergises with anti-PD-1 therapy to induce durable tumour control and immune memory in immune-infiltrated tumours. Mechanistically, both tumour-intrinsic and stromal necroptosis are required. Deletion of Ripk1 or Mlkl in tumour cells, or Mlkl in the stromal compartment, markedly impairs therapeutic efficacy. Moreover, immunologically "cold" tumours can be rendered responsive to ICD-based therapy by STING agonists. These findings demonstrate that the benefit of IAP antagonism with checkpoint blockade critically depends on coordinated necroptosis in both tumour and stromal cells, underscoring the need to integrate tumour microenvironmental context when designing ICD-targeted immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-026-70133-8
  8. Cell Death Differ. 2026 Feb 28.
    Phagocytosis of necroptotic cells optimizes type 1 conventional dendritic cells for induction of a cytotoxic T-cell response.
    Mo D Staal, Zhixian Wang, Douwe M T Bosma, Julia Busselaar, Ellen Schrama, Evert de Vries, Yanling Xiao, Jannie Borst.
      Whether a T-cell response to dead cells arises depends on whether they harbor recognizable antigens, but also how dead cell debris impacts conventional dendritic cells (cDCs). In all tissues, cell debris is continuously phagocytosed by cDCs that can migrate to lymph nodes (LNs) and initiate T-cell responses, depending on their maturation state. The cDC1 lineage excels at antigen cross-presentation, which is required for induction of the CD8+ cytotoxic T-lymphocyte (CTL) response. At steady state, cDC1s undergo homeostatic maturation, which leads to T-cell non-responsiveness. This cDC1 state has recently been defined by ex vivo transcriptomics as resulting from phagocytosis of apoptotic cell debris. Necroptotic (tumor) cell death has been described as more immunogenic than apoptotic cell death, but its impact on cDC maturation has not been defined. In this study, we use an in vitro model to compare side-by-side the impact of well-defined apoptotic versus necroptotic tumor cell debris on the CTL response induced by cDCs, as well as on phenotype and function of both cDC1s and cDC2s. We confirm that cDC2s are less efficient than cDC1s in dead cell phagocytosis and find that they minimally respond to it in terms of gene expression. Apoptotic cell debris is more efficiently phagocytosed by cDC1s than necroptotic cell debris and induces a cDC1 cell state in vitro that has an evident transcriptomic relationship to the homeostatic maturation state defined ex vivo, thus validating our approach. We identify necroptosis as more potent than apoptosis in inducing a CTL response and attribute this to the ability of necroptotic cell debris to induce a specific, transcriptomically defined maturation state in cDC1s, characterized by cytokine and phosphoinositide signaling, cytoskeletal and metabolic activity and functional differentiation. We suggest that this cDC1 signature may be used to diagnose immunogenicity of necroptosis ex vivo.
    DOI:  https://doi.org/10.1038/s41418-026-01689-7
  9. Cell Rep. 2026 Feb 27. pii: S2211-1247(26)00043-4. [Epub ahead of print]45(3): 116965
    Lipocalin 2 orchestrates resistance to ferroptosis via AXL.
    Sabrina Z Wang, J Payton Timken, Ellen S Hong, Sehaj Kaur, Eli Newby, Kristen E Kay, Erin E Mulkearns-Hubert, Daniel J Silver, Juyeun Lee, Joshua B Rubin, James R Connor, Loic P Deleyrolle, Deanna Tiek, Andrew Dhawan, Justin D Lathia.
      Glioblastoma (GBM) remains a lethal tumor, largely due to robust mechanisms that prevent effective induction of cell death. Ferroptosis, a form of iron-dependent cell death, is a promising vulnerability in GBM. Here, we demonstrate that lipocalin-2 (LCN2) suppresses ferroptosis in GBM cells via the receptor tyrosine kinase AXL. LCN2 was elevated in GBM cells compared to lower-grade tumor and non-transformed cells, and Lcn2 knockdown impaired GBM cell fitness and growth in vitro and in vivo. Mechanistically, Lcn2 knockdown triggered ferroptosis, which was specifically rescued with ferroptosis inhibitors but not apoptosis or necroptosis inhibitors. Lcn2 knockdown reduced AXL phosphorylation, which was elevated in GBM patient tumors relative to non-tumor tissue. Notably, the combination of Lcn2 knockdown and pharmacological AXL inhibition extended survival compared to Lcn2 knockdown alone. Taken together, these data reveal a link between LCN2-mediated suppression of ferroptosis with AXL phosphorylation and support this axis as a potential therapeutic target for GBM.
    Keywords:  AXL; CP: cancer; cell death; glioblastoma; lipocalin-2
    DOI:  https://doi.org/10.1016/j.celrep.2026.116965
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