bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–08–30
sixteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. RNF213-dependent lytic destruction of Chlamydia-containing vacuoles activates host cell death pathways.
  2. A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease.
  3. Gasdermin D-mediated delivery of caspase inhibitors to suppress pyroptosis.
  4. Ninjurin-1 mediates hepatic ischemia-reperfusion injury.
  5. Caspase-2 is involved in IFN-γ primed THP-1 derived macrophages cell death through regulating caspase-8 activation.
  6. Structural basis of GSDME pore formation and its regulation by S-palmitoylation.
  7. Cellular Consequences, Citrullination Substrates, and Antigenicity of Targeting PAD4 to Cell Surfaces.
  8. A suite of eight Toxoplasma gondii effectors cooperates to activate the non-canonical NF-κB pathway.
  9. Killing to cure: harnessing poxvirus-driven cell death for viral immunotherapy.
  10. SHARPIN restrains IL-33 release by stromal cells to control ILC2 inflammation.
  11. Cuproptosis: an emerging member of the immunogenic cell death family.
  12. Sublethal Caspase-8 Activation Drives Radiation-Induced Genetic Instability and Oncogenic Transformation Through Endonuclease G and Non-Canonical NF-κB Signaling.
  13. De novo E-cadherin/catenin complex formation controls basal epithelial mechanics and force transmission for apoptotic cell clearance.
  14. Type I IFN-induced IFN-γ instructs monocyte-mediated systemic bacterial protection during type 2 intestinal helminth infection.
  15. A STING inhibitor suppresses ferroptosis through radical-trapping antioxidant activity.
  16. Sneaking in the enemy: infected macrophages permeabilize the endothelium.
  1. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2606688123
    RNF213-dependent lytic destruction of Chlamydia-containing vacuoles activates host cell death pathways.
    Mary S Dickinson, Stephen C Walsh, Robert J Bastidas, Raphael H Valdivia, Jörn Coers.
      The cytokine gamma-interferon promotes antimicrobial cell-autonomous immunity by inducing hundreds of interferon-stimulated genes (ISGs). Among these ISGs is the ubiquitin E3 ligase RNF213 which protects host cells from a wide range of intracellular pathogens including the obligate intracellular bacterium Chlamydia. The human pathogen Chlamydia trachomatis normally employs its secreted virulence effector GarD to evade RNF213-mediated killing. However, in the absence of GarD, RNF213 is recruited to the vacuolar compartment in which C. trachomatis replicates, called the inclusion. Once localized to inclusions, RNF213 ubiquitylates unknown substrates associated with the inclusion membrane and eliminates C. trachomatis through mechanisms that are not yet defined. Ubiquitylation of pathogen-containing vacuoles often results in xenophagy, an autophagy-related defense program. Here, we show that although inclusions can be degraded via xenophagy, this pathway is dispensable for RNF213-dependent inhibition of C. trachomatis replication. In addition to xenophagy, we find that RNF213 targeting can lead to antimicrobial inclusion lysis, thereby releasing bacteria into the host cell cytosol and triggering host cell death. Two cell death pathways occur downstream from RNF213-dependent inclusion rupture: a rapid cell death that despite its apoptosis-like morphology occurs independent of the apoptosis effectors caspase-3 and caspase-7 and instead requires the secreted C. trachomatis protease CPAF, and a slow cell death that is independent of CPAF and instead requires the cytosolic proinflammatory pattern-recognition receptors RIG-I or STING. Thus, RNF213-driven lysis of pathogen-containing vacuoles represents a previously unrecognized mechanism by which RNF213 mediates host defense and triggers a host-pathogen battle over cytosolic immune activation.
    Keywords:  Chlamydia; autophagy; cell death; innate immunity; interferon
    DOI:  https://doi.org/10.1073/pnas.2606688123
  2. Science. 2026 Aug 27. 393(6814): eaeh7112
    A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease.
    Jiyi Pang, Aysha H Al-Ani, Komal M Patel, Yunzhuo Zhou, Samuel N Young, Jinjin Chen, Isabella Kong, Marilou Barrios, James A Rickard, Siqi Chen, Xiuquan Ma, Farzaneh Shojaee, Seong-Beom Kim, Siavash Foroughi, Wayne Cawthorne, Annette V Jacobsen, Asha Jois, Ashley L Weir, Lachlan W Whitehead, Pradeep Rajasekhar, Christopher R Horne, Ruqian Lyu, Lucy J Mather, Raymond K H Yip, Ellen Tsui, Imadh Azeez, Tao Tan, Weiwei Liang, Suresh Sivanesan, Andrew Metz, Ash Patwardhan, Natalie Shea, Guru Iyngkaran, Daniel Schneider, Alexander T Elford, William Beattie, Finlay Macrae, Gianmaria Liccardi, Henning Walczak, Yuxia Zhang, Oliver M Sieber, Tim Spelman, Lisa Giulino-Roth, Michael Christie, Yunshun Chen, Kelly L Rogers, Rory Bowden, Sandra E Nicholson, Kate E Lawlor, Edwin D Hawkins, Britt Christensen, Andre L Samson, James E Vince, James M Murphy.
      Inflammatory bowel disease (IBD) is a chronic condition caused by altered cytokine signaling, maladaptive immunity, dysbiosis, and intestinal barrier dysfunction. Although current therapies aim to correct these imbalances to induce remission, most patients ultimately relapse, suggesting that key pathogenic mechanisms persist. Here, we identified aberrant epithelial cell death signaling as an underlying feature of IBD that arises in patients in remission and on advanced therapy. Mechanistically, nascent inflammation skewed epithelial cells into an M1-macrophage-like transcriptional state that promoted RIPK1-independent necroptotic signaling. This signaling then triggered inducible nitric oxide synthase-assisted mitochondrial apoptosis of absorptive epithelial cells and PUMA-mediated intestinal stem cell death. Thus, aberrant epithelial cell death signaling represents a hallmark of IBD that occurs early in mucosal lesion development, persists despite current therapeutic strategies, and predicts clinical relapse.
    DOI:  https://doi.org/10.1126/science.aeh7112
  3. Nature. 2026 Aug 03.
    Gasdermin D-mediated delivery of caspase inhibitors to suppress pyroptosis.
    Katarzyna M Groborz, Melissa E Truong, Irma Stowe, Katherine E Wickliffe, Bettina Lee, Stefan Bauernfried, Robert S Jones, Emile Plise, Elizabeth S Levy, Ponien Kou, Wyne P Lee, Juan Zhang, Hanna Budayeva, Christopher M Rose, Julia Nguyen, Malgorzata Kalinka, Marcin Drag, Nobuhiko Kayagaki, Kim Newton, Marcin Poreba, Vishva M Dixit.
      Caspase-1, -4, -5 and -11 activate gasdermin D (GSDMD) pores, causing pyroptotic cell death and the release of the interleukins IL-1β and IL-18 (ref. 1). Blocking this pathway holds therapeutic promise for the treatment of inflammatory disorders, but cell-permeable caspase inhibitors have not proved successful in clinical trials2. Here we describe covalent caspase inhibitors that selectively block pyroptosis and IL-1β secretion despite being excluded from healthy cells. These inhibitors did not prevent caspase-driven apoptosis, implying that GSDMD pores facilitated their uptake. Membrane-impermeable dyes entered the cells rescued from pyroptosis, consistent with transient membrane permeabilization by GSDMD pores. Caspase inhibition prevented rather than delayed cell death, consistent with membrane repair mechanisms neutralizing the initial GSDMD pores. Inhibiting caspase-1 and caspase-11 suppressed IL-1β and IL-18 production in a mouse model of endotoxic shock, underscoring the therapeutic potential of exploiting GSDMD pores for targeted caspase inhibition in inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41586-026-10957-y
  4. Sci Adv. 2026 Aug 28. 12(35): eaeg9496
    Ninjurin-1 mediates hepatic ischemia-reperfusion injury.
    Jan Mossemann, Brunna X Martins, Yixuan Zhao, Fiorelle Aguilar, Daria Taskina, Claire J Hur, Diana Nakib, Allen Volchuk, Gang Ye, Danish M Ali, Ali Mirzaesmaeili, Iram Siddiqui, Ghazal Goodarzi, Philip J Bilan, Irma B Stowe, Nobuhiko Kayagaki, Sonya MacParland, Spencer A Freeman, Neil M Goldenberg, Benjamin E Steinberg, Blayne A Sayed.
      Lytic cell death pathways drive hepatic ischemia-reperfusion injury (IRI). The transmembrane protein ninjurin-1 (NINJ1) aggregates in the plasma membrane to permeabilize the cell during multiple cell death pathways implicated in hepatic IRI. We hypothesized that NINJ1 mediates liver IRI and that its inhibition would mitigate injury. We found that NINJ1 is highly expressed in human liver tissue and that its up-regulation and activation correlate with early allograft dysfunction in liver transplant patients. Using a segmental hepatic IRI model in mice and rats, Ninj1 genetic deletion or pharmacologic inhibition diminished acute injury. Mice with hepatocyte- or macrophage-specific Ninj1 knockout had reduced hepatocellular injury following IRI, suggesting that NINJ1 within both populations contributes to the resulting liver injury. Mechanistically, we found that hepatocytes and Kupffer cells are susceptible to hypoxia-induced NINJ1-mediated plasma membrane rupture, which can be pharmacologically prevented. We therefore position NINJ1 as a potential new therapeutic target to limit hepatic IRI, with important implications for liver transplantation.
    DOI:  https://doi.org/10.1126/sciadv.aeg9496
  5. Hum Immunol. 2026 Aug 22. pii: S0198-8859(26)00401-5. [Epub ahead of print]87(10): 112055
    Caspase-2 is involved in IFN-γ primed THP-1 derived macrophages cell death through regulating caspase-8 activation.
    Yushuang Liu, Fei Ding, Xuemei Cao, Jie Chen, Yuling Yang, Jie Shen, Zhuan Li, Shujun Zhang.
      Pro-inflammatory macrophage cell death is essential for resolving inflammation, yet the subtype-specific mechanisms governing this cell death remained unclear. Herein, THP-1-derived macrophages were polarized into pro-inflammatory (M1) or anti-inflammatory (M2) subtypes and exposed to lipopolysaccharide. M1 cells exhibited higher DNA fragmentation, caspase-3 cleavage, and lactate dehydrogenase release. Pharmacologic inhibition or genetic knockdown of caspase-2 effectively attenuated LPS-triggered M1 macrophage cell death. Mechanistic analyses excluded contributions of the mitochondrial apoptotic pathway, as no Bid cleavage, mitochondrial membrane potential dissipation, or rescue effect of cyclosporin A were detected. IFN-γ pretreatment enhanced caspase-8 cleavage, while caspase-2 deficiency consistently blocked caspase-8 activation under diverse death stimuli: LPS, etoposide, tumor necrosis factor-related apoptosis-inducing ligand, and hydrogen peroxide. IFN-γ priming alone triggered caspase-2 cleavage without inducing cell death, and this pre-activated caspase-2 pool strongly amplified subsequent LPS-mediated caspase-8 activation. Collectively, our work identifies a non-canonical, mitochondria-independent caspase-2/caspase-8 axis that selectively drives LPS-induced cell death in IFN-γ-primed THP-1 macrophages. This pathway acts as a self-regulatory feedback loop to eliminate hyper-inflammatory macrophages and maintain immune homeostasis, providing a novel mechanistic framework for understanding subtype-specific macrophage cell death.
    Keywords:  Caspase-2; Caspase-8; Cell death; Interferon gamma; Lipopolysaccharide; Macrophage
    DOI:  https://doi.org/10.1016/j.humimm.2026.112055
  6. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2614339123
    Structural basis of GSDME pore formation and its regulation by S-palmitoylation.
    Gang Du, Julian F Ehrmann, Judy Lieberman, Hao Wu.
      Pyroptosis is defined as gasdermin-mediated lytic programmed cell death. Gasdermin E (GSDME), a substrate of the apoptotic caspase-3, can convert apoptosis into pyroptosis, with critical roles in antitumor immunity and chemotherapy-induced tissue damage. Despite its importance, the structural mechanism of GSDME pore formation and its regulation by posttranslational modifications remain largely unknown. Here, we present the cryo-electron microscopy (cryo-EM) structure at 3.16 Å resolution of the human GSDME N-terminal (NT) pore using proteins expressed from mammalian cells. The structure reveals a GSDME-NT pore assembled mainly as a 28-subunit homo-oligomer, and a dramatic conformational rearrangement from the autoinhibited state, with refolding of the two β-hairpins in each monomer to form a membrane-spanning β-barrel with an acidic conduit. Unexpectedly, we identify endogenous S-palmitoylation of C45, C168, and C180, required for membrane binding and pore formation. In addition, extra cryo-EM densities are visible adjacent to the C45 side chain, potentially corresponding to the flexibly linked palmitate chain. Structure-guided mutagenesis demonstrates that these palmitoylation sites synergistically control pore formation. The structure served as a molecular blueprint for analyzing cancer-associated mutations, known to disrupt GSDME function. These mutations cluster at functional hotspots in the oligomerization interfaces, membrane-contact regions, and the β-barrel, where they disrupt pore integrity. Collectively, our findings establish palmitoylation as an obligatory licensing step for membrane binding and pore formation, provide structural visualization of a palmitoylated gasdermin, and reveal how cancer-associated mutations impair pyroptotic function. This structure and these insights will be useful for developing strategies that target GSDME to treat cancer and inflammatory disease.
    Keywords:  S-palmitoylation; cancer-associated mutations; cryo-EM structure; gasdermin E; pyroptosis
    DOI:  https://doi.org/10.1073/pnas.2614339123
  7. ACS Cent Sci. 2026 Aug 26. 12(8): 1207-1222
    Cellular Consequences, Citrullination Substrates, and Antigenicity of Targeting PAD4 to Cell Surfaces.
    Sophie Kong, Trenton M Peters-Clarke, Corleone S Delaveris, Paul Phojanakong, Veronica Steri, James A Wells.
      Protein arginine deiminase-4 (PAD4) catalyzes hydrolysis of arginine to citrulline in proteins that promote widespread cellular changes that can induce innate immunity and promote cancer. Hyperactivity of PAD4 leads to a form of cell death called NETosis, releasing PAD4 to the extracellular space to promote various autoimmune diseases through the generation of anticitrulline protein antibodies (ACPAs). Little is known about the specific citrullinated substrates that lead to autoimmunity, but there is growing evidence that PAD4 is localized to the cell surface in response to inflammation. Here, we characterize the cellular consequences of exogenous PAD4, showing that it induces morphological changes that increase cell migration, a hallmark of cancer. We then devised a robust proteomics approach to identify PAD4 substrates. We identified ∼ 3000 citrullinated peptides from 1300 proteins upon exogenous addition of PAD4 both inside and outside of cells. This extracellular set can be further augmented by targeting PAD4 to cancer cells using a HER2 binding protein conjugate. Finally, we studied how citrullinated cells can induce a humoral response in vivo to produce ACPAs. We believe these studies further our understanding of cellular consequences of extracellular PAD4 and identify new PAD4 substrates that are potential neoepitopes for ACPA generation.
    DOI:  https://doi.org/10.1021/acscentsci.6c00032
  8. mBio. 2026 Aug 28. e0165226
    A suite of eight Toxoplasma gondii effectors cooperates to activate the non-canonical NF-κB pathway.
    Kenna Berg, Michael W Panas, Samarchith P Kurup, John C Boothroyd, Alex Rosenberg.
      As a master of host-cell reprogramming, Toxoplasma gondii (T. gondii) tachyzoites manipulate diverse signaling networks to establish a niche permissive for long-term infection. While the parasite's subversion of canonical NF-κB signaling (p65/p50) is well established, how infection impacts the non-canonical NF-κB pathway has been largely unexplored. Here, we report that T. gondii infection induces nuclear accumulation of the non-canonical NF-κB subunits RelB and p52 in both human and murine fibroblasts. This response is conserved across both type I and type II parasite genetic backgrounds. We demonstrate that this reprogramming is dependent on the MYR1-mediated export of dense granule effectors. Mechanistically, T. gondii infection drives the depletion of the negative regulator TRAF3, leading to the stabilization of NF-κB-inducing kinase (NIK), phosphorylation of p100, and its subsequent processing into p52. Utilizing a panel of combinatorial knockout parasites, we reveal that no single effector is responsible for this phenotype. Instead, a suite of eight MYR1-dependent effectors, IST, NSM, HCE1/TEEGR, GRA16, GRA18, GRA24, GRA28, and GRA84, functions through a collaborative, additive network to drive most of the non-canonical response. These findings highlight a distributed regulatory strategy used by the parasite to overcome host transcriptional robustness and shape host signaling.
    IMPORTANCE: Toxoplasma gondii infects nearly one-third of the global population and establishes infection by extensively rewiring host immune signaling. While decades of work have focused on how the parasite modulates canonical NF-κB activity, whether it also engages the alternative, non-canonical arm of this pathway has remained unclear. Here, we show that T. gondii tachyzoites activate non-canonical NF-κB signaling, driving nuclear accumulation of RelB/p52 through MYR1-dependent effector export. Unexpectedly, no single effector is responsible. Instead, eight secreted proteins act cooperatively to enable NIK stabilization and engage the non-canonical NF-κB cascade, revealing a networked mode of immune control. This discovery highlights a regulatory logic evolved by the parasite to overcome host transcriptional robustness. Together, these findings identify non-canonical NF-κB activation as a new axis of host-parasite interaction and expand our understanding of how T. gondii reprograms central immune signaling circuits through multi-effector networks.
    Keywords:  MYR translocon; NIK stabilization; RelB; TRAF3; Toxoplasma gondii; dense granule effectors; non-canonical NF-κB; p52
    DOI:  https://doi.org/10.1128/mbio.01652-26
  9. Immunol Lett. 2026 Aug 24. pii: S0165-2478(26)00109-4. [Epub ahead of print] 107235
    Killing to cure: harnessing poxvirus-driven cell death for viral immunotherapy.
    April D'Arcy, Brian J Ferguson.
      Oncolytic virotherapy represents a promising frontier in cancer immunotherapy, leveraging the ability of oncolytic viruses (OVs) to selectively replicate within tumour cells and induce antitumour immunity. In this review, we focus on the clinical development of oncolytic poxviruses and propose that understanding fundamental mechanisms of poxvirus-induced cell death can inform rational clinical development strategies that may avoid challenges and improve outcomes in viral immunotherapy. We discuss the development of Olvimulogene nanivacirepvec (Olvi-Vec), Pexastimogene devacirepvec (Pexa-Vec), and other candidates; the basic biology of poxviruses; their manipulation of host antiviral defences; and the pathways of regulated cell death they can induce, including apoptosis, necroptosis, pyroptosis, and ferroptosis. We examine the potential for optimising oncolysis through targeted genetic modification and combination therapy, with the aim of enhancing the immunogenicity of cell death to overcome the immunosuppressive tumour microenvironment and to enhance adaptive antitumour immune responses.
    Keywords:  Oncolytic virus; immunogenic cell death; poxvirus; vaccinia virus
    DOI:  https://doi.org/10.1016/j.imlet.2026.107235
  10. Sci Adv. 2026 Aug 28. 12(35): eaea2388
    SHARPIN restrains IL-33 release by stromal cells to control ILC2 inflammation.
    Peng Zeng, Xin Mao, Wen Zhang, Jia Li, Zhiqing Wang, Chao Zhang, Qian Li, Yun-Cai Liu.
      Loss of SHARPIN, a component of the linear ubiquitin chain assembly complex (LUBAC), causes systemic inflammation including the accumulation of eosinophils across multiple tissues in mice. However, the mechanisms by which SHARPIN regulates type 2 inflammation remain unclear. Here, we found that SHARPIN deficiency resulted in increased numbers of type 2 innate lymphoid cells (ILC2s) in the lung and other tissues via a cell-extrinsic mechanism. SHARPIN loss enhanced interleukin-33 (IL-33) production by lung stromal cells in vivo and in vitro, thereby promoting ILC2 proliferation. Mechanistically, SHARPIN directly bound IL-33 through its Pleckstrin homology-linker region and restrained IL-33 release independently of its ubiquitination. Combined deficiency of SHARPIN and IL-33 completely reversed ILC2 increase and lung inflammation, but not stromal cell death. Our study reveals a non-canonical, ubiquitin-independent function of SHARPIN as a gatekeeper of IL-33-driven type 2 inflammation.
    DOI:  https://doi.org/10.1126/sciadv.aea2388
  11. Cell Death Differ. 2026 Aug 22.
    Cuproptosis: an emerging member of the immunogenic cell death family.
    Daolin Tang, Gerry Melino, Guido Kroemer.
      
    DOI:  https://doi.org/10.1038/s41418-026-01852-0
  12. Int J Mol Sci. 2026 Aug 19. pii: 7398. [Epub ahead of print]27(16):
    Sublethal Caspase-8 Activation Drives Radiation-Induced Genetic Instability and Oncogenic Transformation Through Endonuclease G and Non-Canonical NF-κB Signaling.
    Chenchen Zhu, Xiaoxiao Li, Chuan-Yuan Li, Renwei Liu, Yifei Wang.
      Apoptosis is traditionally considered a definitive barrier against oncogenesis, as caspase activation typically eliminates damaged and genetically unstable cells. Here, we report that caspase-8, an initiator of extrinsic apoptosis, paradoxically promotes genetic instability and carcinogenesis following exposure to radiation. We observed that a substantial fraction of mammalian cells exposed to ionizing radiation can survive despite caspase-8 activation. This sublethal activation of caspase-8 facilitated persistent DNA damage, which was attenuated by the expression of a dominant-negative caspase-8 (C360A, Casp8DN) or short hairpin RNA (shRNA)-mediated knockdown of caspase-8 in mammalian cells. The facilitative role of caspase-8 in radiation-induced genomic instability was further validated in caspase-8 heterozygous mice. Moreover, inhibition of caspase-8 abolished iron-ion radiation-induced oncogenic transformation in both soft agar and nude mice. Mechanistically, sublethal caspase-8 activation promoted the nuclear translocation of mitochondrial endonuclease G and persistent DNA damage, accompanied by activation of non-canonical nuclear factor κB (NF-κB) signaling. Collectively, our findings demonstrate that caspase-8 can act as a causative driver of radiation-induced malignancy, challenging the dogma of caspases as universal anticancer barriers and providing important insights into the long-term health risks associated with space radiation and radiotherapy.
    Keywords:  caspase-8; endonuclease G; genomic instability; non-canonical NF-κB; oncogenic transformation; radiation
    DOI:  https://doi.org/10.3390/ijms27167398
  13. Nat Commun. 2026 Aug 27. pii: 8900. [Epub ahead of print]17(1):
    De novo E-cadherin/catenin complex formation controls basal epithelial mechanics and force transmission for apoptotic cell clearance.
    Hanna-Maria Häkkinen, Marta Batet, Laura F Bianchi, Senda Jiménez-Delgado, Fabio Pezzano, Stefan Wieser, Luca Ciampa, Esteban Hoijman, Carina Vibe, Sofie Wijma, Verena Ruprecht.
      Beyond serving as cohesive barriers, epithelia clear apoptotic cells to regulate development, homeostasis and inflammation. How epithelial cells remodel their shape during phagocytosis while preserving tissue integrity, and the role of adhesion receptors in this process, remain unclear. Using live in vivo imaging of phagocyte-target interactions in zebrafish (Danio rerio) embryos, we show that basal and apical epithelial domains are mechanically decoupled, enabling engulfment without disrupting tissue cohesion. We identify a dynamic assembly of E-cadherin/catenin complexes at the basal epithelial surface in contact with apoptotic cells. Targeted perturbations reveal two critical functions of de novo E-cadherin/catenin complex formation at the phagocytic synapse: α-catenin acts as a physical linker transmitting actin-generated forces required for engulfment, while p120-catenin restrains Myosin II activity, enabling efficient clearance. We further demonstrate the conservation of E-cadherin-dependent apoptotic cell clearance in the mouse trophectoderm. These findings reveal that the E-cadherin/catenin complex is repurposed at the phagocytic synapse as a mechano-regulator of epithelial efferocytosis beyond its canonical role in tissue cohesion.
    DOI:  https://doi.org/10.1038/s41467-026-76710-1
  14. Sci Immunol. 2026 Aug 28. 11(122): eaeh4719
    Type I IFN-induced IFN-γ instructs monocyte-mediated systemic bacterial protection during type 2 intestinal helminth infection.
    Kelly Wemyss, Lauren M Webb, Hayley M Bridgeman, Ian E Prise, Rufus H Daw, Verena Kästele, Tovah N Shaw, Sabrina Tamburrano, Seona Thompson, Elia D Tait Wojno, Pedro H Papotto, Richard K Grencis, Andrew S MacDonald, Jennifer S Cavet, Joanne E Konkel, Kathryn J Else, John R Grainger.
      Alterations to monocyte output and function occur during infections driving T helper 1 (TH1)-type inflammation. The degree to which monocytes respond to infections initiating alternative types of responses is poorly understood. Here, we describe a distinct state of the monocyte compartment associated with type 2-polarizing intestinal helminths. Unexpectedly, the adapted monocyte state in a type 2 setting was associated with acquisition of an interferon (IFN) signature. This IFN-induced state provided helminth-infected animals with systemic protection against secondary bacterial infection and allowed for the development of effective type 2 immunity. This pathway of monocyte education was distinct from that in TH1 settings and involved an endogenous bacteria-mediated induction of type I IFN that led to adaptive lymphocyte-dependent IFN-γ priming of monocytes. These findings reveal an IFN-driven mechanism of monocyte education that enables the host to be simultaneously protected against type 2 infections at barrier sites and type 1 infections in the circulation.
    DOI:  https://doi.org/10.1126/sciimmunol.aeh4719
  15. Cell Chem Biol. 2026 Aug 27. pii: S2451-9456(26)00291-6. [Epub ahead of print]
    A STING inhibitor suppresses ferroptosis through radical-trapping antioxidant activity.
    Songlin Yin, Yan Li, Ting Mei, Jiayao Li, Xueting Wang, Xiaoxiao Li, Liguo Yang, Junhong Lin, Weijie Ye, Fujia Lu, Weimin Wang.
      Renal ischemia-reperfusion injury (IRI), a leading cause of acute kidney injury, is driven by coordinated inflammatory signaling and ferroptotic cell death, yet effective therapies remain limited. Here, we show that H-151, a covalent stimulator of interferon genes (STING) inhibitor, also suppresses ferroptosis through a STING-independent mechanism. H-151 functions as a broad-spectrum radical-trapping antioxidant that directly scavenges radicals generated during the Fenton reaction, thereby blocking lipid peroxidation. In a murine renal IRI model, H-151 attenuated tissue damage and restored renal function through concurrent inhibition of STING signaling and ferroptosis. These findings establish radical-trapping antioxidant activity as an additional mechanism of H-151 and identify dual inhibition of inflammatory signaling and ferroptosis as a promising therapeutic strategy for IRI and related disorders.
    Keywords:  H-151; STING; ferroptosis; ischemia reperfusion injury
    DOI:  https://doi.org/10.1016/j.chembiol.2026.08.004
  16. Trends Cell Biol. 2026 Aug 26. pii: S0962-8924(26)00161-3. [Epub ahead of print]
    Sneaking in the enemy: infected macrophages permeabilize the endothelium.
    Desmond J Hamilton, Brian C Russo.
      The endothelial barrier provides a defense against bacterial pathogens. Muenkel et al. show that endothelial barrier function increases when macrophages interact with endothelial cells. Conversely, infected macrophages decrease endothelial barrier function and transmigrate more efficiently. These findings show that the endothelium is biomechanically responsive to the infection status of macrophages.
    Keywords:  bacteria; dissemination; endothelial barrier; infection; macrophage; systemic
    DOI:  https://doi.org/10.1016/j.tcb.2026.08.005
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