bims-cediti 2025-08-17 papers

bims-cediti

Biomed News

on Cell death in innate immunity, inflammation, and tissue repair

Issue of 2025–08–17
ten papers selected by
Kateryna Shkarina, Universität Bonn

Gasdermins: multifunctional effectors of membrane permeabilization across cellular compartments.
Stress granule component TIA-1 is a negative regulator of the non-canonical NLRP3 inflammasome.
Caspase-11 regulates systemic inflammation and cell death in a cell-specific manner after trauma with shock.
Lipid nanoparticle delivered intrabodies for inhibiting necroptosis and pyroptosis.
Inflammasome-independent IL-1β activation via staphopain A protease of Staphylococcus aureus.
Stress granule-mediated ZBP1 activation drives necroptotic cell death in non-obstructive azoospermia and testicular aging.
Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.
Phosphatidylethanolamine is a phagocytic ligand implicated in the binding and removal of apoptotic and bacterial extracellular vesicles.
Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA.
An ancient evolutionary origin for IL-1 cytokines as mediators of immunity.

FEBS J. 2025 Aug 10.

Gasdermins: multifunctional effectors of membrane permeabilization across cellular compartments.

Eleonora Margheritis, Nadine Gehle, Katia Cosentino.

  Members of the gasdermin (GSDM) family are pore-forming proteins primarily known for executing inflammatory cell death known as pyroptosis. GSDM-mediated pore formation at the plasma membrane (PM) facilitates the selective secretion of immunomodulatory proteins and nonselective ionic fluxes during pyroptotic signaling. Recent findings suggest that GSDMs also modulate intracellular processes by associating with and altering membranes in various organelles, including mitochondria, lysosomes, endoplasmic reticulum (ER), and the nucleus. These activities may trigger alternative signaling pathways that do not necessarily involve PM perforation. In this review, we explore the diverse mechanisms of GSDM association across organelle membranes and discuss the physiological and pathological implications of GSDM-induced membrane integrity alteration.

Keywords:  gasdermins; inflammation and cancer; organelle membrane alteration; pore formation; pyroptosis regulation

DOI:  https://doi.org/10.1111/febs.70215
bioRxiv. 2025 Jul 16. pii: 2025.07.12.634801. [Epub ahead of print]

Stress granule component TIA-1 is a negative regulator of the non-canonical NLRP3 inflammasome.

Prem Prasad Lamichhane, Aditi, Blake H Neil, Paul B Kilgore, Alfredo G Torres, Ashok K Chopra, Parimal Samir.

Inflammasomes are cytosolic signaling hubs assembled upon pathogen- or damage associated molecular patterns (PAMP and DAMP) sensing by innate immune pattern recognition receptors (PRR). Lipopolysaccharide (LPS) present on the cell wall of gram-negative bacteria is a PAMP that activates caspase 11 (CASP11) dependent nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome (known as non-canonical NLRP3 inflammasome) leading to pyroptosis. Several host factors are shown to promote non-canonical NLRP3 inflammasome activation by making LPS readily available for recognition by CASP11. Here, we report T-cell intracellular antigen-1 (TIA1), an RNA binding protein as a negative regulator of non-canonical NLRP3 inflammasome. Using bone marrow-derived macrophages (BMDMs), we demonstrated that the loss of TIA1 led to an increase in caspase-1 (CASP1) activity in response to cytosolic LPS. A previous study had demonstrated that mice lacking Tia1 are more susceptible to LPS mediated endotoxic shock. Our results provide a potential explanation for this observation by showing loss of TIA1 increases non-canonical NLRP3 inflammasome activation resulting in increased inflammation and pathogenesis during LPS mediated endotoxic shock. Further, TIA1 mediated inhibition of non-canonical NLRP3 inflammasome is independent of TIA1's regulatory role in gene transcription as well as its role in stress granule assembly. TIA1 is also dispensable for activation of the canonical NLRP3 inflammasome as well as AIM2 and NLRC4 inflammasomes. While, the exact mechanism by which TIA1 inhibits non-canonical inflammasome activation remains to be elucidated, our finding that TIA1 is a negative regulator indicates the presence of undiscovered regulatory mechanisms. Future studies will focus on unraveling these mechanisms for developing anti-inflammatory drugs that exploit non-canonical inflammasome activity modulation.

DOI: https://doi.org/10.1101/2025.07.12.634801
J Leukoc Biol. 2025 Aug 16. pii: qiaf121. [Epub ahead of print]

Caspase-11 regulates systemic inflammation and cell death in a cell-specific manner after trauma with shock.

Joud Mulla, Alyssa Gregory, Hong Liao, Bashar Al Matour, Yuzhen Li, Abiha Abdullah, Timothy R Billiar, Melanie J Scott.

  Severe trauma releases damage-associated molecular patterns (DAMPs), which activate the immune system via pattern recognition receptors. This triggers inflammatory cascades that can lead to systemic inflammatory response syndrome, immunosuppression, and multiple organ dysfunction syndrome. Pyroptosis is an inflammatory form of cell death mediated by caspase-11 and gasdermin D (GsdmD). In this study, we examined caspase-11's effects on inflammation, tissue damage and neutrophil infiltration in a model of severe tissue injury. Male C57BL/6J (WT), caspase-11-/-, cell specific caspase-11-/- mice (endothelial specific caspase-11-/- (casp11EC-/-), platelet specific caspase-11-/- (casp11plt-/-), and hepatocyte specific caspase-11-/- (casp11HC-/-) mice, were subjected to polytrauma, consisting of hemorrhagic shock (25% total blood volume removed), liver crush, and bilateral lower extremity injury. At 6h post-polytrauma, blood, plasma and tissues were collected for analysis. Western blot analysis showed caspase-11 and GsdmD cleavage in the lungs and liver in WT mice at 6h after polytrauma. GsdmD cleavage was found to be caspase-11 dependent. Inflammatory mediators, plasma IL-6 and CXCL-1/KC, were significantly increased in caspase-11-/-, casp11HC-/- and casp11EC-/- mice compared to WT controls or casp11plt-/-. Liver damage (ALT/AST) was similar between groups. Circulating neutrophil counts were decreased in caspase-11-/-, but neutrophils and neutrophil myeloperoxidase levels were increased in caspase-11-/- liver compared with WT after polytrauma. Our study identifies an unexpected and novel anti-inflammatory function for caspase-11 in trauma, through the regulation of neutrophil influx into tissues. Our findings underscore the significance of caspase-11 activation early after polytrauma to moderate trauma-induced inflammation.

Keywords:  Inflammation; caspase-11; programmed cell death; tissue injury

DOI:  https://doi.org/10.1093/jleuko/qiaf121
Biochem J. 2025 Aug 05. pii: BCJ-2025-3191. [Epub ahead of print]

Lipid nanoparticle delivered intrabodies for inhibiting necroptosis and pyroptosis.

Veerasikku Gopal Deepagan, Xiuquan Ma, Farzaneh Bazregari, Jiyi Pang, Jan Schaefer, Joanne M Hildebrand, Ruby K Dempsey, Marcel Doerflinger, Christopher A Baldwin, Florian I Schmidt, James M Murphy, Ranja Salvamoser, James E Vince.

  Intrabodies are intracellularly expressed high-affinity protein binders such as nanobodies and monobodies that offer an alternative approach to small molecules. However, the maturation of intrabody technology into new therapeutic modalities has been limited by the availability of a clinically relevant delivery system enabling sufficiently high levels of protein to be expressed in the cytosol. Here, we use lipid nanoparticle (LNP) systems based on clinically approved formulations for the efficient intracellular delivery of mRNAs encoding for intrabodies targeting mixed lineage kinase domain-like pseudokinase (MLKL) and apoptosis-associated speck-like protein containing a CARD (ASC), key mediators of the necrotic cell death modalities, necroptosis and pyroptosis, respectively. LNP delivery of intrabody mRNA resulted in robust protein expression, with a MLKL binding intrabody preventing MLKL membrane translocation and protecting against necroptotic cell death. Similarly, LNP delivery of a bivalent intrabody targeting the inflammasome adaptor protein ASC protected against NLRP3 and AIM2 inflammasome-driven responses, including caspase-1 and IL-1b activation and gasdermin D-driven pyroptotic killing. These findings establish that LNPs harbouring anti-necrotic intrabody mRNAs allow for sufficient intracellular expression to neutralize necrotic cell death signalling and provide a general, clinically relevant, strategy for delivering therapeutic intrabodies into cells.

Keywords:  ASC; Intrabody; MLKL; NLRP3; caspase-1; gasdermin; inflammasome; lipid nanoparticle; mRNA; monobody; nanobody; necroptosis; pyroptosis

DOI:  https://doi.org/10.1042/BCJ20253191
J Biol Chem. 2025 Aug 08. pii: S0021-9258(25)02425-1. [Epub ahead of print] 110574

Inflammasome-independent IL-1β activation via staphopain A protease of Staphylococcus aureus.

Stefan Bauernfried, Tobias Komar, Katja Sterle, Maria C Tanzer, Alexander R Horswill, Matthias Mann, Veit Hornung.

  Interleukin-1β (IL-1β) is a pivotal mediator of innate immunity, essential for orchestrating the acute inflammatory response. While the canonical activation of IL-1β involves cleavage of its inactive precursor (pro-IL-1β) by the inflammatory cysteine protease caspase-1, certain bacterial proteases, such as those secreted by group A Streptococcus and Pseudomonas aeruginosa, can also activate pro-IL-1β. In this study, we demonstrate that infection of human N/TERT-1 immortalized keratinocytes by Staphylococcus aureus induces IL-1β processing independently of the classical inflammasome pathways. Biochemical analysis reveals that a secreted factor from S. aureus cleaves pro-IL-1β at a site proximal to the canonical caspase-1 cleavage site, rendering the cytokine bioactive. Specifically, we identify the secreted cysteine protease staphopain A as responsible for this cleavage. Our findings highlight a novel mechanism of inflammasome-independent IL-1β activation through microbial proteases, expanding the understanding of pathogen-host interactions in immune responses, specifically in the skin.

Keywords:  Interleukin-1β; NLRP1; Staphylococcus aureus; inflammasome; keratinocytes; microbial proteases; staphopain A

DOI:  https://doi.org/10.1016/j.jbc.2025.110574
Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2514837122

Stress granule-mediated ZBP1 activation drives necroptotic cell death in non-obstructive azoospermia and testicular aging.

Hongen Lei, Dianrong Li, Jie Chen, Baowen Du, Kaiju Jiang, Tao Xu, Hu Han, Weiliang Fan, Long Tian, Xiaodong Wang.

  Male infertility remains a major unmet medical challenge, with poorly defined molecular mechanisms and no effective therapies. Here, we identify a stress granule-mediated necroptotic pathway as a key driver of non-obstructive azoospermia, a severe form of male infertility marked by the loss of spermatogenesis. Environmental or physiological stress activates eIF2α kinases, inducing stress granule formation and the recruitment of ZBP1 and RIPK3 into a cytoplasmic complex. This assembly triggers RIPK3 activation, MLKL phosphorylation, and necroptotic death of spermatogonia and Sertoli cells. Genetic ablation of Zbp1 or Ripk3 protects mice from heat-induced testicular degeneration, establishing their essential role in stress-induced testicular damage. Importantly, activation of this pathway is also observed in aged human testes, linking stress-responsive necroptosis to both pathological infertility and the broader process of reproductive aging. These findings reveal an unrecognized mechanism that couples cellular stress responses to regulated cell death in the male reproductive system.

Keywords:  ZBP1; necroptosis; non-obstructive azoospermia; stress granule; testis aging

DOI:  https://doi.org/10.1073/pnas.2514837122
Nature. 2025 Aug 13.

Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.

Wulf Tonnus, Francesca Maremonti, Shubhangi Gavali, Marlena Nastassja Schlecht, Florian Gembardt, Alexia Belavgeni, Nadja Leinung, Karolin Flade, Natalie Bethe, Sofia Traikov, Anne Haag, Danny Schilling, Sider Penkov, Melodie Mallais, Christine Gaillet, Claudia Meyer, Melika Katebi, Anushka Ray, Louisa M S Gerhardt, Anne Brucker, Jorunn Naila Becker, Mirela Tmava, Lisa Schlicker, Almut Schulze, Nina Himmerkus, Andrej Shevchenko, Mirko Peitzsch, Uladzimir Barayeu, Sonia Nasi, Juliane Putz, Kenneth S Korach, Joel Neugarten, Ladan Golestaneh, Christian Hugo, Jan Ulrich Becker, Joel M Weinberg, Svenja Lorenz, Bettina Proneth, Marcus Conrad, Eckhard Wolf, Bernd Plietker, Raphaël Rodriguez, Derek A Pratt, Tobias P Dick, Maria Fedorova, Stefan R Bornstein, Andreas Linkermann.

Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss1, the hallmark of end-stage renal disease2-4. For decades, it has been known that female kidneys are less sensitive to AKI5,6. Acute tubular necrosis involves dynamic cell death propagation by ferroptosis along the tubular compartment7,8. Here we demonstrate abrogated ferroptotic cell death propagation in female kidney tubules. 17β-oestradiol establishes an anti-ferroptotic state through non-genomic and genomic mechanisms. These include the potent direct inhibition of ferroptosis by hydroxyoestradiol derivatives, which function as radical trapping antioxidants, are present at high concentrations in kidney tubules and, when exogenously applied, protect male mice from AKI. In cells, the oxidized hydroxyoestradiols are recycled by FSP19,10, but FSP1-deficient female mice were not sensitive to AKI. At the genomic level, female ESR1-deficient kidney tubules partially lose their anti-ferroptotic capacity, similar to ovariectomized mice. While ESR1 promotes the anti-ferroptotic hydropersulfide system, male tubules express pro-ferroptotic proteins of the ether lipid pathway which are suppressed by ESR1 in female tissues until menopause. In summary, we identified non-genomic and genomic mechanisms that collectively explain ferroptosis resistance in female tubules and may function as therapeutic targets for male and postmenopausal female individuals.

DOI: https://doi.org/10.1038/s41586-025-09389-x
Curr Biol. 2025 Aug 06. pii: S0960-9822(25)00952-2. [Epub ahead of print]

Phosphatidylethanolamine is a phagocytic ligand implicated in the binding and removal of apoptotic and bacterial extracellular vesicles.

Ava A Kavianpour, Sina Ghasempour, Kirsten J Meyer, Trieu Le, Ruiqi Cai, Pedro Elias Marques, Justin R Nodwell, Spencer A Freeman.

  The efficient recognition and removal of apoptotic cells and extracellular vesicles (EVs) by phagocytes is critical to prevent secondary necrosis and maintain tissue homeostasis. Such detection involves receptors and bridging molecules that recognize aminophospholipids-normally restricted to the inner leaflet of healthy cells-which become exposed on the surface of dead cells and the vesicles they produce.1,2,3,4,5 A majority of studies focus on phosphatidylserine (PS), for which there are well-established receptors that either bind to the lipid directly or indirectly via intermediary proteins.6,7,8 Phosphatidylethanolamine (PE) is even more prevalent than PS in the inner leaflet of mammalian cells9 and also becomes exposed by the action of scramblases during cell death,10,11 though little is known about the effects of PE once scrambled. Here, we report that PE can itself serve as a phagocytic ligand for macrophages by engaging CD300 family receptors. CD300a and CD300b specifically modulated the binding and uptake of PE particles, and this process involved immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors and spleen tyrosine kinase (Syk). For bacteria, which contain PE but largely lack PS in their membranes, we report that PE engagement enabled the binding and uptake of spheroplasts and bacterial extracellular vesicles (BEVs) that were unsheathed by the cell wall. The inflammatory responses of macrophages to PE particles containing lipopolysaccharide (LPS) were also curtailed by CD300a expression. Based on these observations, we posit that the direct recognition of PE facilitates mechanisms of clearance that stand to have a broad impact on the immune response.

Keywords:  CD300a; CD300b; Syk; TMEM16F; actin cytoskeleton; extracellular vesicles; phagocytosis; phosphatidylethanolamine; phosphatidylserine

DOI:  https://doi.org/10.1016/j.cub.2025.07.043
Science. 2025 Aug 14. 389(6761): eadp3971

Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA.

Lauren Murphy, Jeanne Inchauspé, Giampiero Valenzano, Pamela Holland, Nikolaos Sousos, Hayley L Belnoue-Davis, Rong Li, Natalie J Jooss, Camelia Benlabiod, Eleanor Murphy, Zohar Etzioni, Emelie Shepherd, Lucy Denly, Sujata Biswas, Lin Chen, Jennifer O'Sullivan, Michael P Rimmer, Abdullah O Khan, Christina Simoglou Karali, Nadia Nasreddin, Ian S Hitchcock, Milka Koupenova, Skirmantas Kriaucionis, Jim R Hughes, Eric O'Neill, Manu Vatish, Paul Rees, Simon Leedham, Michael Desborough, Adam J Mead, Benjamin Schuster-Böckler, Christopher D Gregory, Bethan Psaila.

Platelets are anucleate blood cells vital for hemostasis and immunity. During cell death and aberrant mitosis, nucleated cells release DNA, resulting in "cell-free" DNA in plasma (cfDNA). An excess of cfDNA is deleterious. Given their ability to internalize pathogen-derived nucleic acids, we hypothesized that platelets may also clear endogenous cfDNA. We found that, despite lacking a nucleus, platelets contained a repertoire of DNA fragments mapping across the nuclear genome. We detected fetal DNA in maternal platelets and cancer-derived DNA in platelets from patients with premalignant and cancerous lesions. As current liquid biopsy approaches utilize platelet-depleted plasma, important genetic information contained within platelets is being missed. This study establishes a physiological role for platelets that has not previously been highlighted, with broad translational relevance.

DOI: https://doi.org/10.1126/science.adp3971
bioRxiv. 2025 Jul 18. pii: 2025.07.17.662885. [Epub ahead of print]

An ancient evolutionary origin for IL-1 cytokines as mediators of immunity.

Francisco Fontenla-Iglesias, Tse-Mao Lin, Amelia G Williams, Sabyasachi Das, Chia-Yen Lee, Jonathan P Rast, Max D Cooper, Katherine M Buckley, Sebastian D Fugmann.

Inflammation is a hallmark of immune responses. Its mechanistic underpinnings in mammals are well-defined: pro-inflammatory cytokines of the interleukin 1 (IL-1) superfamily establish and support microenvironments that promote immune cell activities. Despite a growing number of reports on inflammatory processes and components of the IL-1 signaling axis in several invertebrate lineages, orthologs of these central cytokines have not been detected outside of the jawed vertebrates. Here, protein structure prediction algorithms were applied to identify genes encoding a family of IL-1 proteins with homologs throughout Eumetazoa (termed "IL-1anc" to reflect their ancestral evolutionary origin). Using Petromyzon marinus (sea lamprey) and Strongylocentrotus purpuratus (purple sea urchin) as model systems, we demonstrate that IL-1anc proteins share important features with mammalian IL-1α/IL-1β including expression patterns, protein localization, and processing. Together, our data indicate that the IL-1 superfamily and associated circuitry represent a foundational module of animal immunity that far predates the jawed vertebrates.

DOI: https://doi.org/10.1101/2025.07.17.662885