bims-cediti 2026-05-17 papers

bims-cediti

Biomed News

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

Issue of 2026–05–17
eleven papers selected by
Kateryna Shkarina, Universität Bonn

CRY-NLRP3 complexes define a circadian checkpoint controlling inflammasome activation.
Monitoring Inflammasome Activity Through ASC Speck Formation in THP-1 ASC-GFP Cells.
ISG15 negatively regulates RIPK3-mediated cell death and viral pathogenesis.
Mechanisms and functions of large extracellular vesicle biogenesis.
Phosphorylation at Ser182 and Thr186 blocks GSDMD pyroptotic activity.
Alarmin cues and regulated cell death calibrate mucosal immunoglobulin A responses and virologic control after intranasal whole-virion inactivated influenza vaccination.
NDRG3 is essential for sustaining antigen-driven T cell responses by protecting against restimulation-induced cell death.
Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: A case study with Bid.
An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection.
Ferroptosis inhibition enhances liver and lung graft function.
Soluble bacterial lipopeptides suppress gasdermin D-associated IL-33 release in keratinocytes and atopic dermatitis in mice.

bioRxiv. 2026 Feb 28. pii: 2026.02.26.708242. [Epub ahead of print]

CRY-NLRP3 complexes define a circadian checkpoint controlling inflammasome activation.

Léa Bardoulet, Delphine Burlet, Hubert Leloup, François Virard, Sabine Hacot, Elsa G Guillot, Nouhaila El Kasmi, Camille Cosson, Lyvia Moudombi, Marie-Cécile Michallet, Arnaud Bonnafoux, Mélina Gautier, Agnès Tissier, Katja A Lamia, Bénédicte F Py, Virginie Petrilli, Anne-Laure Huber.

Innate immune sensors such as the NLRP3 inflammasome can trigger inflammatory responses within minutes, raising the question of how circadian clocks influence such rapid decisions. Here, we identify a protein-level circadian checkpoint that links core clock components to NLRP3 inflammasome activation. We show that NLRP3 associates with the circadian repressors CRY1 and CRY2, forming oscillatory complexes that restrain inflammasome activation and rapidly dissociate upon stimulation. Pharmacological stabilization of CRY proteins preserves CRY-NLRP3 association and attenuates inflammasome assembly, IL-1β secretion and pyroptotic cell death in primary human macrophages. In synchronized macrophages, both NLRP3 inflammasome activation and its inhibition by the NLRP3 inhibitor MCC950 vary with circadian time. Finally, a subset of NLRP3 variants reported in cohorts of patients with Cryopyrin-Associated Periodic Syndromes (CAPS), a group of hereditary fever syndromes caused by mutations in NLRP3, weaken CRY binding and are associated with altered time-of-day patterns of inflammasome activation and MCC950 responsiveness. Together, these findings define CRY-NLRP3 complexes as a circadian checkpoint that modulates inflammasome activity and drug response, revealing time of day as a critical dimension of NLRP3-driven inflammation.

DOI: https://doi.org/10.64898/2026.02.26.708242
Methods Mol Biol. 2026 ;3002 201-210

Monitoring Inflammasome Activity Through ASC Speck Formation in THP-1 ASC-GFP Cells.

Timothy Muusse, Sarah Little.

  Inflammasome activation and signaling are hallmarks of immune activation and cellular response. Understanding the complex mechanisms involved in the formation of the NLRP3 inflammasome is vital to accurately evaluating potentially anti-inflammatory molecules. The oligomerization of ASC is a well-documented indicator of inflammasome activation, and ASC-GFP allows the visualization of these "specks." Here, we detail a higher throughput methodology for monitoring inflammasome activation and screening potential anti-inflammatory compounds utilizing an Incucyte® live cell imager. It provides a platform to observe cell activation and cell death in real-time. Cells can be visualized from initial plating through to inflammasome-induced cell death, granting insights into inflammasome activation kinetics and previously unknown toxicities.

Keywords:  ASC; Anti-inflammatory; Incucyte®; Inflammasome; THP-1 cells

DOI:  https://doi.org/10.1007/978-1-0716-5056-1_18
Cell Rep. 2026 May 15. pii: S2211-1247(26)00438-9. [Epub ahead of print]45(5): 117360

ISG15 negatively regulates RIPK3-mediated cell death and viral pathogenesis.

Yi-Chieh Perng, Jessica M C Warsaw, Sachendra S Bais, Bradley E Hiller, Marissa C Locke, David J Morales-Heil, Chaoqun Li, Alissa R Young, Kristen J Monte, Robert E Schmidt, Douglas R Green, Yi-Nan Gong, Deborah J Lenschow.

  Necroptosis, a form of programmed, inflammatory necrosis, plays an important role in viral-host defense and inflammation. The receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway mediates necroptosis. Yet, the mechanisms that control necroptosis to limit immunopathology are poorly understood. Here, we report that interferon-stimulated gene 15 (ISG15) negatively regulates RIPK3-mediated cell death, including necroptosis, and limits immunopathology during chikungunya virus (CHIKV) infection. ISG15-deficient mice infected with CHIKV display increased levels of necroptosis, resulting in elevated proinflammatory cytokine and chemokine production, leading to increased lethality. This dysregulated host response is fully prevented when MLKL or RIPK3 is ablated in Isg15-/- mice. Mechanistically, ISG15 non-covalently associates with the RIPK3 necrosome in an RIP homotypic interaction motif (RHIM)-dependent manner, regulating necroptosis downstream of CHIKV infection, tumor necrosis factor (TNF), lipopolysaccharide (LPS), and poly(I:C) stimulation. These results demonstrate a role for ISG15 in limiting immunopathology during infection by modulating necroptosis-dependent inflammation and pathogenesis.

Keywords:  CHIKV; CP: immunology; CP: microbiology; ISG15; MLKL; RIPK3; chikungunya virus; homeostasis; immunopathology; necroptosis

DOI:  https://doi.org/10.1016/j.celrep.2026.117360
Nat Cell Biol. 2026 May 15.

Mechanisms and functions of large extracellular vesicle biogenesis.

Stephanie F Rutter, Jascinta P Santavanond, Alan Y Hsu, Taylon F Silva, Dolores Di Vizio, Ivan K H Poon.

Owing to the ability of extracellular vesicles (EVs) to encapsulate and transfer biomolecules for intercellular communication, EVs are recognized as promising candidates as biomarkers and therapeutic delivery vehicles. Small EVs (S-EVs), below 200 nm in diameter, have previously been the major focus in the EV field, but large EVs (L-EVs) are gaining considerable interest, with many distinct subsets of L-EVs having been described in the past few years. Here we review L-EV biogenesis from a context-specific perspective, focusing on the biological settings that drive L-EV formation. We also discuss the roles of L-EVs in facilitating the removal of unwanted cellular content and intercellular communication. Finally, we identify key challenges in the L-EV field and discuss future investigations towards harnessing L-EVs for diagnostic and therapeutic applications.

DOI: https://doi.org/10.1038/s41556-026-01940-w
Cell Signal. 2026 May 12. pii: S0898-6568(26)00252-4. [Epub ahead of print] 112599

Phosphorylation at Ser182 and Thr186 blocks GSDMD pyroptotic activity.

Mengxue Li, Jixuan Xu, Guangyuan Li, Qingmin He, Yamin Xing, Mingyu Peng, Weishan Zhang, Ting Zhang, Chunxiao Gao, Honglin Chen, Ruihong Wang, Xiaoke Zheng, Xin Xing, Hongqiao Zhang, Zisen Zhang, Pengyuan Zheng, Xiufeng Chu.

  Pyroptosis, mediated by gasdermin D (GSDMD), is a form of programmed cell death highly associated with inflammatory and immune diseases. While its activation is well-studied, the precise negative regulatory mechanisms remain to be fully elucidated. Here, we sought to investigate the regulatory role of phosphorylation on GSDMD activity. We identified that phosphorylation at murine Ser182/Thr186 (Ser181/Ser185 in humans) constitutes an inhibitory regulatory mechanism for the cytolytic activity of the GSDMD N-terminal fragment (GD-NT). Mechanistically, using structural modeling and site-directed mutagenesis, we found that phosphorylation at Ser182/Thr186 did not affect the auto-inhibition of full-length GSDMD or its cleavage by caspase-11. However, it severely impaired the pyroptotic activity of GD-NT by affecting its membrane localization and oligomerization. Consequently, the double phosphomimetic mutant of GD-NT (S182D/T186D) was non-lytic to cells. Thus, we define Ser182/Thr186 as critical post-cleavage checkpoint sites for inhibiting pyroptosis. This discovery enriches the regulatory network of GSDMD and provides potential therapeutic targets for modulating inflammatory diseases.

Keywords:  GSDMD; Phosphorylation; Pyroptosis; Ser182/Thr186

DOI:  https://doi.org/10.1016/j.cellsig.2026.112599
Int Immunol. 2026 May 14. pii: dxag023. [Epub ahead of print]

Alarmin cues and regulated cell death calibrate mucosal immunoglobulin A responses and virologic control after intranasal whole-virion inactivated influenza vaccination.

Eita Sasaki, Hideki Asanuma, Yoshimasa Takahashi, Hideki Hasegawa.

  How tissue damage cues and regulated cell death programs instruct antigen-specific mucosal IgA after vaccination remains incompletely defined. Using a mouse model of intranasal whole-virion inactivated influenza vaccination, we identify two proximal inputs that shape antibody output and virologic control: epithelial necroptosis-associated interleukin-33 release and a macrophage death-program switch that unmasks interleukin-1α. Immunization was accompanied by lung cell death, interleukin-33 release, and the induction of antigen-specific mucosal immunoglobulin A. In alveolar macrophages, vaccine uptake required phagocytosis and was associated with lysosomal destabilization and cathepsin B activity, which were linked to interleukin-1α release under conditions that favored regulated necrotic cell death. Consistent with this, pharmacologic inhibition of caspases shifted the dominant death program in alveolar macrophages and was associated with enhanced B cell activation in the cervical lymph nodes and increased immunoglobulin A-producing cell-like populations. At the functional level, caspase inhibition augmented vaccine-elicited protection, including reduced lung viral titers and attenuated pathology after homologous challenge and improved control of a within-subtype drift influenza A virus challenge strain; these enhancements were partly dependent on interleukin-1α. Together, these data support a model in which alarmin cues and regulated cell death pathways in the lung modulate the magnitude of mucosal immunoglobulin A responses and contribute to virologic control after intranasal whole-virion inactivated influenza vaccination. Limitations include reliance on pharmacologic pathway modulation and a mouse intranasal whole-virion inactivated influenza vaccine model; thus, mechanistic generalization beyond this context should be made cautiously.

Keywords:  IL-1α; IL-33; alveolar macrophage; intranasal vaccine; necroptosis

DOI:  https://doi.org/10.1093/intimm/dxag023
J Immunol. 2026 May 14. pii: vkag070. [Epub ahead of print]215(5):

NDRG3 is essential for sustaining antigen-driven T cell responses by protecting against restimulation-induced cell death.

Brian J Stack, Susan M Kaech.

  During the response to infections and pathogenic challenges, T cells must expand profoundly and be resilient to repetitive restimulation to clear the ongoing assault and protect the host. This process of prolific expansion is tightly regulated to quickly provide a robust pool of pathogen-fighting T cells, yet also limit excessive expansion to prevent inadvertent damage to host tissues. Restimulation-dependent pro-growth and pro-death signals help regulate this delicate balance of T cell expansion to maintain both host and T cell homeostasis. We have discovered that NDRG3 is a critical determinant of whether T cells proliferate or undergo apoptosis during repetitive restimulation under antigen-driven T cell expansion. CD8+ T cells lacking NDRG3 exhibit severely impaired expansion in vivo in response to both viral infections and tumor challenges. We show that NDRG3 is essential for T cell survival during antigen restimulation by protecting T cells from restimulation-induced cell death (RICD), while it has only a marginal impact on T cell survival in contexts with limited antigen restimulation. Mechanistically, NDRG3 safeguards repetitively stimulated T cells from RICD by constraining FAS-mediated pro-death signaling through caspase-8. Furthermore, NDRG3 overexpression enhanced T cell infiltration into tumors, improving their tumor-controlling capacity. Collectively, these findings establish NDRG3 as a novel, indispensable regulator of T cell responses to foreign challenges. Additionally, this work identifies NDRG3 as a previously undescribed regulator of RICD in T cells and reveals NDRG3 as a potential target for autoimmune disorders and chimeric antigen receptor T cell treatment for cancer.

Keywords:  NDRG3; T cells; restimulation-induced cell death

DOI:  https://doi.org/10.1093/jimmun/vkag070
Proc Natl Acad Sci U S A. 2026 May 19. 123(20): e2527963123

Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: A case study with Bid.

Christina Elsner, Anton Hanke, Oscar Vadas, Francesco Luigi Gervasio, Enrica Bordignon.

  Intrinsic apoptosis is a form of cell death which is activated, executed, and inhibited by the Bcl-2 protein family. The structural basis of the inhibition mechanisms remains elusive. Here, we characterize the ensemble structural model of the inhibitory Bcl-xL/tBid complex at the mitochondrial membrane by probing interresidue distances and dynamic solvent accessibilities complemented by integrative modeling and molecular dynamics simulations. We show that Bcl-xL and tBid form a heterodimer anchored to the membrane by the C-terminal helix of Bcl-xL. The BH3 domain of tBid is wedged between the exposed hydrophobic groove of Bcl-xL and the membrane headgroups, while tBid's C-terminal helices remain dynamically engaged with the bilayer. This dynamic architecture sheds light on the mechanism of indirect inhibition of apoptosis.

Keywords:  Bcl-2 proteins; DEER; MD simulations; apoptosis; mitochondria

DOI:  https://doi.org/10.1073/pnas.2527963123
Nat Immunol. 2026 May 12.

An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection.

S Lebon, A Habshush Menachem, N Davidzohn, A Katz, N Wigoda, T Braun, D Yahalomi, R Rotkopf, V Holiar, T Dadosh, S Levin-Zaidman, N Dezorella, I Goliand, M Kupervaser, S Leebhoff, N Blumberger, D Hoffman, M Grunewald, Y Levin, Y Haberman, M Hofree, M Biton.

Intestinal stem cells (ISCs) are essential for sustaining epithelial renewal and barrier integrity, yet their role in orchestrating defense against enteric pathogens remains unclear. Here we identify a stem cell-intrinsic immune mechanism whereby Lgr5+ ISCs detect intracellular Salmonella enterica and activate an inflammasome-dependent differentiation program. Using fluorescent-labeled S. enterica, single-cell transcriptomics, fate mapping, organoid models, and genetic perturbations, we show that invaded ISCs undergo rapid reprogramming toward antimicrobial peptide-enriched Paneth cells via apoptosis-associated Speck-like protein containing a CARD (ASC, encoded by Pycard)-mediated inflammasome signaling. This fate switch enhances epithelial antimicrobial capacity and restricts pathogen persistence in the crypt. The response is Salmonella-specific and conserved in human intestinal organoids. Moreover, the invasion-associated transcriptional signature is enriched in ISCs from patients with Crohn's disease. Our findings reveal that ISCs act as active sensors of bacterial invasion and initiate epithelial remodeling through inflammasome signaling, highlighting stem cell plasticity as a frontline innate immune strategy.

DOI: https://doi.org/10.1038/s41590-026-02514-6
Cell. 2026 May 08. pii: S0092-8674(26)00459-9. [Epub ahead of print]

Ferroptosis inhibition enhances liver and lung graft function.

Geraldine Veeckmans, Lene Devos, Nicholas Gilbo, Dieter Van Beersel, Camilla Scarpellini, Joris Blondeel, Magali Walravens, Greta Klejborowska, Caroline Lanthier, Michele Wölk, Sebastian Müller, Christine Gaillet, Ludovic Colombeau, Behrouz Hassannia, Matthias Längin, Martin Bender, Jan-Michael Abicht, Bruno Reichart, Hans De Winter, Maria Fedorova, Raphaël Rodriguez, Jacques Pirenne, Laurens J Ceulemans, Ina Jochmans, Koen Augustyns, Diethard Monbaliu, Arne Neyrinck, Tom Vanden Berghe.

  Ischemia-reperfusion injury (IRI) is a major clinical challenge in transplantation, vascular surgeries, myocardial infarction, and stroke. Disruption of energy and redox homeostasis triggers ferroptosis, a regulated, iron-dependent form of cell death, leading to organ dysfunction. We identify an early and transient increase of lipid peroxidation in human liver transplants and validate it as a therapeutic target. FXT-001, a ferroptosis inhibitor with dual radical and iron-trapping activity, provides robust protection in preclinical models, including ex situ perfusion of porcine liver and lung grafts. In a split ex vivo machine perfusion setting using declined human donors, FXT-001 treatment preserves graft viability, whereas untreated lungs deteriorate. We also develop FXT-002 and FXT-003 with enhanced pharmacokinetic and safety profiles. These findings support the use of ferroptosis inhibitors as a therapeutic strategy in transplantation and other IRI-associated conditions.

Keywords:  FXT-001; ex situ machine perfusion; ferroptosis; human graft; iron; ischemia-reperfusion injury; liver; lung; porcine graft; radical-trapping antioxidant

DOI:  https://doi.org/10.1016/j.cell.2026.04.024
Nat Commun. 2026 May 13.

Soluble bacterial lipopeptides suppress gasdermin D-associated IL-33 release in keratinocytes and atopic dermatitis in mice.

Helen Williams, Ryo Muko, Emily Wright, Reynard Spiess, Hiroshi Matsuda, Akane Tanaka, Peter D Arkwright, Joanne L Pennock.

The rising prevalence of allergic diseases over the last century has been linked to smaller families and the shift of populations from countryside to cities, leading to reduced exposure to environmental bacteria. We previously demonstrated that Staphylococcus aureus-derived Second immunoglobulin-binding protein (Sbi) drives type 2 immune responses and atopic dermatitis (AD). Here we show that contrary to current dogma, soluble lipopeptides, particularly diacylated lipopeptides released by Gram-positive bacteria in their stationary phase suppress type 2 immune responses in vitro and eczema in the NC/Tnd mouse model. The immunomodulatory activity of these lipopeptides is destroyed by lipoprotein lipase. Their mechanism of immunomodulation is independent of CD14 and toll-like receptor (TLR) signaling but rather associated with inhibition of caspase/gasdermin D (GSDMD)-mediated release of the interleukin (IL)-33 alarmin from the nucleus. Our findings help to explain why exposure to environmental bacteria and topical application of bacterial commensals suppresses AD. We suggest that soluble bacterial lipopeptides could be developed into a novel class of therapeutics for treatment of allergic diseases.

DOI: https://doi.org/10.1038/s41467-026-72376-x