bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–08–23
thirteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. Novel gain-of-function mutation in dysferlin causes vesicle trafficking defect and IL-1 mediated autoinflammation.
  2. Mechanisms underlying propagation of ferroptotic cell death.
  3. Vitamins tune cell death thresholds.
  4. RAD51 stabilizes neutrophil extracellular traps to compartmentalize inflammation.
  5. Anchoring of perforin-2 via the transmembrane domain is required for antigen escape into the cytosol.
  6. Highly efficient derivation of functional human induced pluripotent stem cell-derived macrophages under serum-free conditions to study innate immune responses.
  7. Expulsion of nuclear DNA to the cytoplasm after viral entry: A mechanism for activation of the cGAS pathway.
  8. Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
  9. YBX1 regulates RNA polymerase III transcripts to prevent inflammation.
  10. Canonical and noncanonical autophagy in immunity.
  11. A genome-wide map of the genetic network in monocytes that regulates type I interferon induction by the cGAS-STING pathway.
  12. Megakaryocyte emperipolesis arms neutrophils via intracellular provisioning.
  13. Bacterial effector modifies host messenger RNA to promote virulence.
  1. medRxiv. 2026 Aug 07. pii: 2026.08.04.26358821. [Epub ahead of print]
    Novel gain-of-function mutation in dysferlin causes vesicle trafficking defect and IL-1 mediated autoinflammation.
    Farzana Bhuyan, Clinton Bradfield, Amitava Roy, Adriana A de Jesus, Mohammad Arif Rahman, Benjamin Schwarz, Anjelika Gasilina, Andre Rastegar, Gaurav Sachin, Christopher L Friend, Kanika Chopra, Kat Uss, Ryan Kissinger, Sara Alehashemi, Sundar Ganesan, Nathan T Brandes, Ian S Lacroix, Vinod Nair, Jacqueline M Leung, Clayton Winkler, Juraj Kabat, Steven M Holland, Philip J Kahn, Douglas B Kuhns, John Hammer, Ronit Herzog, Deborah Consolini, Iain Fraser, Raphaela Goldbach-Mansky.
      De novo mutations underlying early-onset systemic autoinflammatory diseases have identified key regulators of innate immunity, including pathways that drive IL-1-mmediated inflammation. Here we describe two unrelated girls presenting in infancy with systemic inflammation and sterile lung abscesses, who harbor the same de novo gain-of-function mutation in dysferlin ( DYSF ; p.P1449L) Myeloid expression of DYSF P1449L enhances COP-I binding, promotes dysferlin retention in the ER-Golgi, and disrupts vesicle trafficking and membrane homeostasis. Dysferlin-mutant monocytes and M2-like macrophages exhibit ectopic perinuclear NLRP3 inflammasome activation, increased IL-1β production, and inflammatory cell death. Mutant M2-like macrophages further display defects in membrane expansion, exocytosis, efferocytosis, and debris clearance, promoting neutrophil recruitment and DAMP-signal amplification that culminate in sterile abscess formation. These findings identify dysferlin as a regulator of membrane homeostasis in myeloid cells, establish defective membrane-stress adaptation as trigger of NLRP3 inflammasome activation, and define a novel IL-1 mediated autoinflammatory disease caused by gain-of-function DYSF mutations.
    DOI:  https://doi.org/10.64898/2026.08.04.26358821
  2. Nat Cell Biol. 2026 Aug 21.
    Mechanisms underlying propagation of ferroptotic cell death.
    Francesca Maremonti, Alireza Dehdari, Nadja Leinung, Derek A Pratt, Andreas Linkermann.
      Necrotic zones in tissues occur in a wide variety of diseases. Ferroptosis, an iron-promoted necrosis driven by lipid peroxidation, has been identified as a key cell death modality in these conditions. Cells undergoing ferroptosis are unique in that they can induce death in their neighbours. Here we review salient aspects of ferroptosis propagation on the molecular, cellular and tissue levels. Cell death propagation is restricted by several ferroptosis-suppression systems. Glutathione peroxidase 4 (GPX4) and ferroptosis-suppressor protein 1 (FSP1) are now well established as master regulators, but various additional systems dictate ferroptosis sensitivity. We discuss how these mechanisms contribute to the suppression of cell death propagation, and how they cause various tissues to be more or less resistant to ferroptosis propagation. Understanding tissue-specific dynamics is critical to interpret the beneficial effects and limitations of future therapeutic approaches for ferroptosis-driven diseases.
    DOI:  https://doi.org/10.1038/s41556-026-02053-0
  3. Trends Cell Biol. 2026 Aug 21. pii: S0962-8924(26)00158-3. [Epub ahead of print]
    Vitamins tune cell death thresholds.
    Rui Kang, Guido Kroemer, Daolin Tang.
      Vitamins are essential micronutrients traditionally viewed as passive cofactors that sustain cellular homeostasis. Emerging evidence challenges this notion, identifying vitamins as active regulators of cell fate that tune the threshold for regulated cell death. Through coordinated control of redox balance, metabolic pathways, and signaling networks, vitamins shape cellular susceptibility to diverse death programs. Their effects are highly context-dependent, enabling both prosurvival and prodeath outcomes depending on dose, cell type, and metabolic state. Recent studies further uncover noncanonical mechanisms linking vitamins to lipid remodeling, membrane trafficking, and organelle integrity. Collectively, these advances establish vitamins as dynamic modulators of cellular vulnerability and highlight their potential as therapeutic targets for selectively manipulating cell death in disease.
    Keywords:  cell death; metabolism; redox; signaling; vitamins
    DOI:  https://doi.org/10.1016/j.tcb.2026.08.002
  4. Science. 2026 Aug 20. 393(6813): eaed9286
    RAD51 stabilizes neutrophil extracellular traps to compartmentalize inflammation.
    Lorenza Iolanda Tsansizi, Sophie Yihan Guan, Iker Valle Aramburu, Rajvee Shah Punatar, Thomas J Williams, Yihe E Qiao, Anna Reed, Darius Armstrong-James, Stephen C West, Venizelos Papayannopoulos.
      Neutrophil extracellular traps (NETs) feature a branched chromatin architecture whose origin and function remain unknown. We found that NET branching is mediated by RAD51, a protein generating DNA junctions during DNA recombination repair. Pharmacological inhibition, RAD51 knockdown, or GEN1 and RuvC resolvase treatment reduced branching and destabilized NETs, whereas RAD51 up-regulation by different stimuli generated NETs with variable stability. RAD51 inhibition during murine pulmonary Aspergillus fumigatus infection dismantled NETs and reduced lung cytokines. However, the increased accumulation of NET components in the circulation led to interleukin-6 (IL-6) induction in circulating monocytes that exacerbated type 2 inflammation and asthma. Extracellular plasma DNA correlated with IL-6 and eotaxin in human aspergillosis. By structurally stabilizing NETs, RAD51 compartmentalizes inflammation to thwart aberrant systemic immune activation, linking DNA repair to inflammation.
    DOI:  https://doi.org/10.1126/science.aed9286
  5. EMBO J. 2026 Aug 19.
    Anchoring of perforin-2 via the transmembrane domain is required for antigen escape into the cytosol.
    Marco Laub, Ritika Chatterjee, Patrycja Kozik.
      Perforin-2 is a pore-forming protein localised to the endocytic compartments of dendritic cells and macrophages. It is reported to perform two distinct functions during immune responses: attacking intravacuolar pathogens, and forming pores in endocytic compartments to enable cytosolic delivery of antigens during cross-presentation. The molecular mechanisms that regulate perforin-2 remain unknown. Here, we address how cross-presenting dendritic cells control pore formation in phagosomes while maintaining the integrity of their endocytic compartments. We demonstrate that perforin-2 undergoes extensive proteolytic processing involving multiple endocytic proteases. Although the transmembrane anchor has been proposed to protect host membranes by orienting pores towards bacterial targets, we find that endocytic escape is mediated by full-length, membrane-anchored perforin-2 rather than by the proteolytically released ectodomain. Moreover, we show that perforin-2-mediated antigen translocation does not require low pH, explaining how perforin-2 can form pores in cross-presenting dendritic cells which do not acidify their phagosomes. Our findings point to a critical role of the transmembrane anchor in perforin-2 biology and suggest that perforin-2 employs distinct mechanisms of pore formation during anti-bacterial defence and cross-presentation.
    DOI:  https://doi.org/10.1038/s44318-026-00903-z
  6. J Innate Immun. 2026 Aug 19. 1-20
    Highly efficient derivation of functional human induced pluripotent stem cell-derived macrophages under serum-free conditions to study innate immune responses.
    Hani Hosseini Far, Le Ying, Linden J Gearing, Rachelia R Wibawa, Trevor J Wilson, Ali Motezadian, Michelle D Tate, Elizabeth L Hartland, Christine A Wells, Paul J Hertzog.
       INTRODUCTION: Macrophages are essential components of innate immunity, serving as a frontline defense against pathogens and maintaining tissue homeostasis. Human induced pluripotent stem cell (iPSC)-derived macrophages (iMacs) provide a powerful platform for studying human innate immunity and macrophage biology. Here, we describe a robust, reproducible, efficient serum-free and feeder-free protocol for generating functional iMacs and characterizing their innate immune properties.
    METHODS: A 30-day monolayer culture system was utilized to continually generate hematopoietic progenitor cells (HPCs) from iPSCs starting on day 9, followed by macrophage differentiation over 21 days. Macrophage identity was assessed by flow cytometry, while functional assays evaluated phagocytosis and cytokine production, including interferons (IFNs). Transcriptomic profiling was performed by RNAseq across differentiation stages and following IFN stimulation.
    RESULTS: The optimized protocol consistently yielded iMacs with >99% purity, expressing canonical macrophage markers including CD14, CD16, CD163, HLA-DR, and CD11b. iMacs demonstrated robust phagocytic capacity and cytokine production in response to microbial stimuli. RNA sequencing revealed distinct gene signatures during differentiation, highlighting key transitions from pluripotency to progenitors, then to mature macrophages. iMac transcriptomes aligned with tissue-resident macrophage profiles, supporting their relevance for modelling tissue-specific immunity. iMacs displayed differential interferon responses, with a strong response to type I IFNs.
    CONCLUSION: This study establishes a highly efficient and robust protocol for generating functional human iPSC-derived macrophages, providing a versatile model for investigating innate immunity, host-pathogen interactions, and interferon signaling.
    DOI:  https://doi.org/10.1159/000553371
  7. Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2614472123
    Expulsion of nuclear DNA to the cytoplasm after viral entry: A mechanism for activation of the cGAS pathway.
    Nicolás Romero, Hyung Suk Oh, Max E Mertens, Maria Ericsson, Kyle N Stearns, Anne Moscona, David M Knipe.
      Cells respond to viral infection by induction of numerous innate and other host responses to block infection in that cell and surrounding cells. The mechanism(s) by which nuclear replicating DNA viruses and certain RNA viruses elicit responses through the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) cytoplasmic DNA sensor has been elusive. We report here that early events during herpes simplex virus 1 infection induce blebbing of nuclear DNA into the cytoplasm, recruitment of cGAS colocalization with the cytoplasmic DNA, activation of interferon regulatory factor 3, and induction of type 1 human interferon in normal human fibroblasts and keratinocytes. With HSV-1, this is dependent on viral binding and fusion with the surface membrane but independent of transport of the input viral DNA to the nucleus. Infections by herpes simplex virus 2, human cytomegalovirus, or human parainfluenza virus 3 also induce nuclear DNA blebbing, consistent with entry by surface fusion inducing this effect. Extrusion of nuclear DNA through nuclear envelope breaks upon viral entry by fusion represents a mechanism for cells to respond to the physical and/or molecular changes in the infected cell during infection.
    Keywords:  herpes simplex virus; host response; innate immunity; interferon signaling; viral entry
    DOI:  https://doi.org/10.1073/pnas.2614472123
  8. Sci Adv. 2026 Aug 21. 12(34): eaed6318
    Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
    Joan Blanco-Fernandez, Miriam Lisci, Mads M Foged, Chloé Chapuis, Tim Pflästerer, Tatjana Kleele, Alexis A Jourdain.
      Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response.
    DOI:  https://doi.org/10.1126/sciadv.aed6318
  9. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2605741123
    YBX1 regulates RNA polymerase III transcripts to prevent inflammation.
    Tania I Strilets, Sarah E Dremel, Mariano A Garcia-Blanco.
      Tolerance of endogenous nucleic acids is crucial for cellular homeostasis and when perturbed can lead to immune dysregulation. RNA-binding proteins (RBPs) bind, modify, and compartmentalize endogenous RNAs to prevent their recognition by the innate immune system. We found that loss of a highly abundant RBP, the cold shock domain containing Y-box binding protein 1 (YBX1), results in the spontaneous induction of an IL6/STAT3 inflammatory response and the upregulation of interferon-stimulated genes. A meta-analysis of other studies reveals that the depletion of YBX1 orthologs and paralogs results in a similar proinflammatory gene signature, suggesting a conserved role of Y-box proteins in maintaining innate immune homeostasis. Among RNAs that interact with YBX1, we tested whether endogenous RNA polymerase III (RNAP III) transcripts stimulate innate immune signaling when YBX1 is depleted. We demonstrate that the inflammatory responses induced by the loss of YBX1 are abrogated by inhibiting RNAP III transcription and RIG-I signaling. Hence, we hypothesize that by regulating RNAP III transcripts, YBX1 prevents their recognition by the innate immune system, uncovering a role of this RBP in maintaining cellular homeostasis and tolerance to endogenous RNAs. The conservation of this phenotype across YBX1 orthologs and paralogs argues that RNA shielding by cold shock domain proteins represents an evolutionarily conserved solution to the problem of endogenous RNA immunogenicity.
    Keywords:  RNA; RNA polymerase III; YBX1; immunity; inflammation
    DOI:  https://doi.org/10.1073/pnas.2605741123
  10. Immunity. 2026 Aug 17. pii: S1074-7613(26)00316-X. [Epub ahead of print]
    Canonical and noncanonical autophagy in immunity.
    Vojo Deretic.
      Canonical and noncanonical autophagic processes are integrated with innate and adaptive immunity and sterile or pathogen-induced inflammation. In canonical autophagy, double-membrane autophagosomes modified by ubiquitin-like ATG8 proteins in a process termed membrane atg8ylation sequester and eliminate intracellular targets such as invading microbes, defunct organelles, aggregates, and inflammatory molecules. Recently, a plethora of noncanonical processes that entail membrane atg8ylation of various intracellular organelles other than autophagosomes have been linked to immunity. This has led to confounding interpretations and conflation of diverse processes as autophagy. Here, we posit that these are divergent manifestations of a common ancestral homeostatic process of membrane atg8ylation and provide an overview of how they affect immunity and inflammation. These relationships are evident in model organisms and are reflected in human genetic predispositions to diseases with immune components. The membrane atg8ylation pathways affect acute and chronic inflammation, infections, autoimmunity, cancer, neurodegeneration, metabolic syndrome, diabetes, and other disorders.
    Keywords:  autophagy; immunity; infection; membrane atg8ylation
    DOI:  https://doi.org/10.1016/j.immuni.2026.07.017
  11. Sci Signal. 2026 Aug 18. 19(951): eadx3808
    A genome-wide map of the genetic network in monocytes that regulates type I interferon induction by the cGAS-STING pathway.
    Emil Aagaard Thomsen, Jian Zhao, Ryo Narita, Luther J Davis, David Olagnier, Søren R Paludan, Jacob Giehm Mikkelsen.
      Type I interferons (IFNs) are induced by pattern recognition receptors (PRRs) of the innate immune system to protect against foreign pathogens and malignant transformation, and their production must be tightly regulated to balance antiviral defense with tissue homeostasis. To define the genetic network that governs IFN regulation, we conducted genome-wide CRISPR screens for genes that positively or negatively regulated IFNB1 gene expression induced by the PRR cGAS and its downstream effector STING, in both unprimed THP-1 cells and cells primed with IFN-α to mimic an ongoing inflammatory response. Distinct subsets of genes affected IFNB1 induction in the unprimed and primed states, and many regulators had not previously been associated with IFN responses, thereby linking IFNB1 regulation to various cellular pathways. For example, we found that the NCoR/SMRT corepressor complex components TBL1XR1 and HDAC3 cooperated to support IFNB1 expression, with HDAC3 promoting activation of the kinase TBK1, an essential driver of type I IFN responses. These datasets are a resource for identifying genes associated with type I IFN-related inborn errors of immunity and cancer and for developing therapies to modulate STING signaling in interferonopathies and other conditions of dysregulated type I IFN.
    DOI:  https://doi.org/10.1126/scisignal.adx3808
  12. bioRxiv. 2026 Aug 09. pii: 2026.08.04.742780. [Epub ahead of print]
    Megakaryocyte emperipolesis arms neutrophils via intracellular provisioning.
    Julia K Kuehn, Geon Ho Bae, Roxane Darbousset, Frank Y Huang, Rebecca M Hall, Josephin E Schiffer, Dhruv Miglani, Spoorthi Balu, Alexandra Wactor, Dorsaf Ghaloussi, Olga Barreiro, Li Guo, Andrew S Weyrich, Simon J Cleary, Matthias Gunzer, Yoichiro Iwakura, David P Hoytema van Konijnenburg, Joseph E Italiano, Mark R Looney, Éric Boilard, Wolfgang Bergmeier, Pierre Cunin, Peter A Nigrovic.
      Neutrophils are phenotypically heterogenous cells that mediate host defense and tissue homeostasis. Here, we identify emperipolesis - the evolutionarily conserved process by which neutrophils pass through megakaryocytes - as a phenotypically transformative route of egress from bone marrow. By intravital microscopy and 3-D histology, we show that the rapid form emperipolesis is markedly enhanced under inflammatory conditions. Neutrophils exit from megakaryocytes directly to the blood, acquiring exosomes enriched in proteins related to metabolism, migration, and immune function. This transfer induces a distinct neutrophil phenotype characterized by enhanced glycolysis, oxidative phosphorylation, cytokine release, and longevity. Correspondingly, emperipolesis-educated neutrophils display accelerated migration in vitro and in vivo . Disrupting emperipolesis does not alter circulating neutrophil abundance but impairs neutrophil infiltration into inflamed tissues, including Pseudomonas aeruginosa -infected lung. These findings establish emperipolesis as a mechanism by which megakaryocytes amplify neutrophil-mediated immunity.
    DOI:  https://doi.org/10.64898/2026.08.04.742780
  13. Cell Host Microbe. 2026 Aug 21. pii: S1931-3128(26)00319-7. [Epub ahead of print]
    Bacterial effector modifies host messenger RNA to promote virulence.
    Kathleen McCaffrey, Stefan Gaussmann, Garrett Z Ng, Tristan Dewald, Mark Helm, Frederic Allain, Elizabeth L Hartland.
      Bacterial pathogens harbor specialized secretion systems that inject effector proteins into the host cell to establish infection and disease. While many bacterial effectors post-translationally modify proteins to influence host responses, the extent to which effectors modify host RNA is currently unknown. Here we performed RNA-interactome capture (RIC) to isolate effectors bound to host cellular messenger RNA (mRNA) during Legionella pneumophila infection. RIC identified an uncharacterized effector, FadA (Lpw16921), which localized to the host-cell nucleus and interacted with host mRNAs at uracil (U)-rich RNA motifs. FadA exhibited NADPH-oxidase activity that mediated 8-oxo-guanine (oxo8G) modifications of mRNA substrates, resulting in oxidative damage and inhibition of translation. Infection with L. pneumophila harboring wild-type FadA, but not a catalytically inactive mutant, increased oxo8G modifications, suppressed cytokine responses, and promoted bacterial persistence in vivo. Our findings demonstrate the potential for a secreted effector to post-transcriptionally modify host mRNA as a mechanism to promote bacterial virulence.
    Keywords:  8-oxo-guanine; Legionella pneumophila; RNA damage; RNA modification; RNA-interactome capture; bacterial pathogen; effector protein; epitranscriptome; protein translation
    DOI:  https://doi.org/10.1016/j.chom.2026.07.018
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