bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–12–14
thirteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. Identification of an IRF-ZBP1-caspase-8-NINJ1 axis in driving PANoptosis and pathology during alcohol-associated liver disease.
  2. A metabolic cell death program downstream of SARM1 couples NAD+ depletion to BAX activation and APAF1 degradation.
  3. Microtubule detyrosination links inflammasome activation to apoptotic cell death in macrophages upon influenza A virus infection.
  4. cFLIP suppresses caspase-1- and MLKL-independent perinatal lethality driven by auto-processing impaired caspase-8 D387A.
  5. Hyperthermia induces reductive stress in murine macrophages.
  6. GADD45β inhibits RIPK3-mediated NF-κB activation by interfering with NEMO-RIPK1-RIPK3 interactions.
  7. Caspase-8 expression in CD8+ T cells promotes pathogen restriction in the brain during Toxoplasma gondii infection.
  8. Programmed cell death pathways coordinate neutrophil and macrophage clearance in zebrafish and are differentially exploited by Salmonella Typhimurium.
  9. Aryl hydrocarbon receptor-induced activation of AIM2 inflammasome is mediated by MOMP and MPT: A vital therapeutic pathway for inflammation.
  10. DAMP-driven trained immunity: metabolic and epigenetic reprogramming in critical illness and chronic inflammation.
  11. An antimicrobial daptide from human skin commensal Staphylococcus hominis protects against skin pathogens.
  12. A circadian checkpoint relocates neutrophils to minimize injury.
  13. NEDD 4 Pyre-fighters to extinguish inflammation: NEDD4L ubiquitinates Gasdermin D and Gasdermin E to dampen pyroptosis.
  1. Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2525296122
    Identification of an IRF-ZBP1-caspase-8-NINJ1 axis in driving PANoptosis and pathology during alcohol-associated liver disease.
    Qiang Qin, Wen Chen, Clay D King, Sivakumar Prasanth Kumar, Chadi A El Farran, Peter Vogel, Rebecca E Tweedell, Thirumala-Devi Kanneganti.
      Innate immunity provides the critical first line of defense against infection and sterile triggers. Inflammatory cell death is a key component of the innate immune response to clear pathogens, but excessive or aberrant cell death can induce inflammation, cytokine storm, and pathology, making it a central molecular mechanism in inflammatory diseases. Alcohol-associated liver disease (ALD) is one such inflammatory disease, and the specific innate immune mechanisms driving pathology in this context remain unclear. Here, by leveraging RNA-seq and protein expression analyses in tissues from clinical samples, we identified increased expression of the innate immune sensor ZBP1 in patients with ALD. ZBP1 expression correlated with ALD progression in patients and that ethanol induced ZBP1-dependent lytic cell death, PANoptosis, in immune (macrophages, monocytes, and Kupffer cells) and nonimmune cells (hepatocytes). Mechanistically, the interferon regulatory factors (IRFs) IRF9 and IRF1 upregulated basal ZBP1 expression. Activation of ZBP1 led to PANoptosis via caspase-8 and cell membrane rupture through NINJ1, independent of gasdermin D, gasdermin E, and MLKL. In mouse models of ALD, ZBP1-deficient mice were significantly protected from disease pathology and liver damage. Furthermore, the expressions of ZBP1 and NINJ1 were upregulated in both liver and serum samples from patients with ALD, implicating these molecules as potential biomarkers. Overall, our findings establish the critical role of the IRF-ZBP1-caspase-8-NINJ1 axis in driving inflammatory cell death, PANoptosis, suggesting that targeting these molecules will have therapeutic potential in ALD and other inflammatory conditions.
    Keywords:  ZBP1; alcohol; alcohol-associated liver disease; caspase; inflammation
    DOI:  https://doi.org/10.1073/pnas.2525296122
  2. Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2522444122
    A metabolic cell death program downstream of SARM1 couples NAD+ depletion to BAX activation and APAF1 degradation.
    Weilong Pan, Dejia Guo, Daiyuan Liu, Xiaodong Wang.
      SARM1 is a neuronal Nicotinamide adenine dinucleotide (NAD+) hydrolase that drives axonal degeneration and neuronal death by depleting NAD+, yet how NAD+ loss triggers axon loss and cell death has remained unclear. Here, we define a nonapoptotic death program downstream of endogenous SARM1 activation and NAD+ loss using a genetically tractable nonneuronal eHAP cell model. Upon NAD+ depletion, BAX is activated but caspase activation is suppressed due to APAF1 degradation via the E3 ligase HERC4, effectively uncoupling mitochondrial outer membrane permeabilization from apoptosome formation. Mechanistically, NAD+ depletion inhibits mTOR/AKT signaling, destabilizing MCL1 and relieving BAX from repression. We further identified Neurofibromatosis type II, NF2, as a regulator that promotes SARM1 transcription through the Hippo-YAP/TAZ pathway. The SARM1-dependent BAX activation and the role of NF2 in axon degradation were validated in neuronal models of axon degeneration. Together, these findings reveal how SARM1-driven metabolic collapse rewires cell death execution, positioning BAX, MCL1, APAF1, NF2, and HERC4 as core effectors in a nonapoptotic degenerative pathway linking metabolic stress to neurodegeneration.
    Keywords:  APAF1; Apoptosis; BAX; NAD+; SARM1
    DOI:  https://doi.org/10.1073/pnas.2522444122
  3. J Virol. 2025 Dec 09. e0184725
    Microtubule detyrosination links inflammasome activation to apoptotic cell death in macrophages upon influenza A virus infection.
    Joyeeta Kar, Mikako Hirohama, Kotono Nakayama, SangJoon Lee, Atsushi Kawaguchi.
      The tubulin code, defined by diverse post-translational modifications of microtubules, fine-tunes microtubule dynamics, regulating downstream cellular signaling. Among these, detyrosination of α-tubulin has long been recognized, yet its upstream regulation and physiological roles in viral infection remain unclear. Here, we show that influenza A virus (IAV) infection induces heterogeneous cell death morphologies in macrophages, including pyroptotic "ghost" cells and apoptotic beaded apoptopodia. Beaded apoptopodia were enriched with detyrosinated α-tubulin, a long-lived, stable microtubule modification generated by enzymatic removal of the C-terminal tyrosine residue. We found that the detyrosination was dependent on caspase-1-mediated inflammasome signaling. Pharmacological inhibition of vasohibin-1 (VASH1) suppressed detyrosination without affecting viral replication, identifying VASH1, but not VASH2, as the predominant carboxypeptidase responsible for this modification upon IAV infection. Overexpression of VASH1 enhanced detyrosination and shifted cell death from pyroptosis toward apoptosis. These findings uncover a cytoskeletal pathway that modulates inflammasome signaling toward immunologically silent apoptosis, thereby limiting inflammatory cell lysis. This mechanism highlights the physiological significance of VASH1-mediated detyrosination in shaping host responses to viral infection.
    IMPORTANCE: Programmed cell death is an essential host response to viral infection, but whether infected macrophages undergo inflammatory or non-inflammatory forms of death has important consequences for disease progression. In this study, we found that influenza A virus infection induces a modification of microtubules known as detyrosination, which stabilizes their structure. This change was driven by the host enzyme vasohibin-1 through activation of the inflammasome, a key signaling complex that normally promotes inflammatory cell death. Remarkably, enhanced detyrosination shifted dying cells away from inflammatory membrane rupture toward apoptosis, an immunologically silent cell death pathway that preserves membrane integrity. Our findings identify microtubule detyrosination as a stress-induced host response during influenza A virus infection, highlighting a novel mechanism by which cytoskeletal modification influences the outcome of infection.
    Keywords:  apoptosis; detyrosination; inflammasome; influenza virus; microtubule
    DOI:  https://doi.org/10.1128/jvi.01847-25
  4. Cell Death Differ. 2025 Dec 12.
    cFLIP suppresses caspase-1- and MLKL-independent perinatal lethality driven by auto-processing impaired caspase-8 D387A.
    Kim Newton, Katherine E Wickliffe, Allie Maltzman, Debra L Dugger, Juan Reyes, Natasha Bacarro, Søren Warming, Neha Rohatgi, Rohit Reja, Joshua D Webster, Vishva M Dixit.
      Death ligands, including FAS ligand (FASL) and tumor necrosis factor (TNF), trigger apoptosis by promoting caspase-8 dimerization and activation. Impaired FAS signaling causes unconventional lymphocytes to accumulate, resulting in lymphadenopathy. Although autoprocessing of caspase-8 is considered important for apoptosis, autoprocessing-deficient Casp8D387A/D387A mice do not develop lymphadenopathy. We show that this is because heterodimers of caspase-8 D387A and cFLIP, besides suppressing MLKL-driven necroptosis, can also induce apoptosis. Interestingly, caspase-8 D387A elicited MLKL- and caspase-1-independent intestinal atrophy and perinatal lethality in mice lacking cFLIP. Caspase-8 D387A interacted with FADD and RIPK1 in the intestine, where there was aberrant cleavage of N4BP1 and caspase-3, plus enhanced NF-κB signaling. Eliminating FADD, the adaptor protein that promotes caspase-8 oligomerization, prevented this perinatal lethality. Collectively, our results suggest that cFLIP forms heterodimers with caspase-8 D387A to promote apoptosis in some contexts, while limiting the activity of caspase-8 D387A homodimers in others.
    DOI:  https://doi.org/10.1038/s41418-025-01650-0
  5. Biochim Biophys Acta Mol Basis Dis. 2025 Dec 09. pii: S0925-4439(25)00483-1. [Epub ahead of print] 168133
    Hyperthermia induces reductive stress in murine macrophages.
    Rong Xu, Xiu-Wen Liang, Qi-Hai Cai, Yuan-Wen Cai, Nuo Sun, Ya-Ping Li, Zi-Jian Shi, Bo Hu, Xian-Hui He, Qing-Bing Zha, Dong-Yun Ouyang.
      Hyperthermia induces heat stress (HS) and injuries in various human organs, or even leads to mortality, yet the underlying mechanism is incompletely uncovered. Our study revealed that HS in macrophages induced concurrent activation of pyroptotic, apoptotic, and necroptotic pathways, and the formation of PANoptosome-like complexes. However, these processes proceeded independently of ROS, as the ROS scavengers N-acetyl cysteine and mito-TEMPO failed to prevent the cell death (PANoptosis) despite effectively suppressing oxidative stress. Instead, HS caused reductive stress marked by NADPH accumulation and thioredoxin (Trx) system dysfunction. Trx1 aggregation impaired redox regulation, leading to aberrant disulfide bonding in mitochondrial proteins (e.g., Drp1, Bcl-2). The Trx reductase exogenous substrate DTNB partially rescued cell viability by restoring redox balance, confirming Trx failure as a key driver of cytotoxicity. Notably, such reductive stress was accompanied by DNA damage and mitochondrial injury during HS. Pharmacologic intervention revealed that pan-caspase inhibition by IDN-6556 abrogated the reductive stress and its consequences (ROS production, DNA damage, and mitochondrial injury), and suppressed the pyroptotic/apoptotic signaling and lytic cell death. However, the caspase inhibition alone triggered compensatory receptor-interaction protein 3 (RIPK3) activation, necessitating dual inhibition with GSK'872 (RIPK3 inhibitor) to fully block PANoptotic cell death. In vivo validation showed protection of the IDN-6556/GSK'872 combination against HS-induced injury on the intestines through reduced DNA damage and PANoptosis suppression. Our study reveals that reductive stress-mediated Trx dysfunction, not oxidative stress, underlies HS-induced PANoptosis. Dual targeting of caspases and RIPK3 provides a novel therapeutic avenue against heat shock-associated diseases.
    Keywords:  Heat stress; Macrophages; Mitochondrial damage; PANoptosis; Reactive oxygen species; Reductive stress
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168133
  6. Cell Death Discov. 2025 Dec 07.
    GADD45β inhibits RIPK3-mediated NF-κB activation by interfering with NEMO-RIPK1-RIPK3 interactions.
    Carmela Casale, Alete Colella, Miriam Cruoglio, Serena Mirra, Emanuela Iaccarino, Maria Brigida Lioi, Francesca Fusco, Annamaria Sandomenico, Antonio Leonardi, Francesca Zazzeroni, Alessandra Pescatore.
      Necroptosis is a highly inflammatory form of regulated cell death driven by Receptor-Interacting Protein Kinase 3 (RIPK3), which plays a crucial role in immune responses, inflammatory diseases, and tumor microenvironment modulation. Beyond driving cell death via MLKL phosphorylation, RIPK3 also activates NF-κB signaling, promoting cytokine production and immunogenic responses. However, the regulatory mechanisms governing RIPK3-dependent NF-κB activation remain largely unclear. Here, we identify Growth Arrest and DNA Damage-inducible β (GADD45β) as a novel regulator of RIPK3 activities. We show that GADD45β directly binds RIPK3 in a RHIM-independent manner, interfering with NEMO-RIPK1-RIPK3 complex formation and limiting RIPK3-mediated NF-κB activation. Furthermore, inducible expression of GADD45β selectively suppresses RIPK3-induced proinflammatory signaling without promoting caspase-dependent apoptosis and markedly reduces CXCL8 (IL-8) production during necroptotic stimulation. GADD45β also improves long-term cellular survival under sustained inflammatory stress. Our findings reveal GADD45β as a critical modulator of RIPK3-driven immune responses and suggest a potential therapeutic strategy for fine-tuning immunogenic cell death.
    DOI:  https://doi.org/10.1038/s41420-025-02894-y
  7. Sci Adv. 2025 Dec 12. 11(50): eadz4468
    Caspase-8 expression in CD8+ T cells promotes pathogen restriction in the brain during Toxoplasma gondii infection.
    Lydia A Sibley, Maureen N Cowan, Abigail G Kelly, NaaDedee A Amadi, Isaac W Babcock, Sydney A Labuzan, Michael A Kovacs, Samantha J Batista, John R Lukens, Tajie H Harris.
      Cell death is an integral restriction mechanism against intracellular pathogens. We have previously reported extensive cell death in the brain during infection with the intracellular parasite, Toxoplasma gondii. Here, we focus on the role of caspase-8, a regulator of extrinsic apoptosis, during T. gondii infection. We find that Casp8-/-Ripk3-/- mice have increased brain parasite burden in comparison to controls and succumb to infection despite the generation of robust immune responses. We observed that neurons, astrocytes, and CD8+ T cells had high rates of parasite interactions in Casp8-/-Ripk3-/- mice compared to wild-type mice. While Casp8 deficiency in neurons and astrocytes did not affect control of infection, deletion of Casp8 in CD8+ T cells led to impaired survival, increased parasite burden, and direct infection of CD8+ T cells in the brain. We conclude that in addition to well-characterized effector functions, CD8+ T cells use caspase-8 to control T. gondii in the brain.
    DOI:  https://doi.org/10.1126/sciadv.adz4468
  8. Cell Death Dis. 2025 Dec 08.
    Programmed cell death pathways coordinate neutrophil and macrophage clearance in zebrafish and are differentially exploited by Salmonella Typhimurium.
    Juan M Lozano-Gil, Annamaria Pedoto, Ana M Conesa-Hernández, María Ocaña-Esparza, Victoriano Mulero, Sylwia D Tyrkalska.
      Programmed cell death (PCD) is essential for immune cell homeostasis and host defense, yet its role in neutrophil and macrophage elimination during bacterial infections remains poorly understood. Using the zebrafish model, which offers unique in vivo imaging and genetic manipulation advantages, we dissected the contribution of pyroptosis, apoptosis, and necroptosis to the regulation of neutrophil and macrophage fate during homeostasis and infection with Salmonella enterica serovar Typhimurium (ST). Under basal conditions, all three PCD pathways cooperated to control immune cell turnover. Upon infection, zebrafish larvae mounted a type III secretion system (T3SS)-independent emergency myelopoietic response that increased myeloid cell numbers. However, the pathogen rapidly counteracted this response by promoting neutrophil death through Nlrp3-mediated pyroptosis and Caspase-3-dependent apoptosis, and macrophage killing via Ripk1-dependent necroptosis-both driven by its T3SS. While blocking pyroptosis prevented neutrophil loss, it also increased host susceptibility due to impaired bacterial clearance, whereas inhibition of apoptosis or necroptosis enhanced resistance, as these pathways are dispensable for controlling infection. These findings demonstrate how ST exploits distinct PDC mechanisms to evade innate immunity and underscore their differential potential as therapeutic targets in intracellular bacterial infections.
    DOI:  https://doi.org/10.1038/s41419-025-08291-8
  9. Cell Rep. 2025 Dec 10. pii: S2211-1247(25)01445-7. [Epub ahead of print]44(12): 116673
    Aryl hydrocarbon receptor-induced activation of AIM2 inflammasome is mediated by MOMP and MPT: A vital therapeutic pathway for inflammation.
    Min Chen, Zhiwei Liang, Mengyuan Sun, Zhen Chen, Chun Peng, Suliman Khan, Mubbashar Abbas, Dongmei Chen, Shuyu Xie.
      Understanding how mitochondrial dysfunction (MD) triggers damage-associated molecular pattern (DAMP) signaling could advance therapies for inflammatory diseases. While aryl hydrocarbon receptor (AHR) is implicated in MD-related inflammation, its mechanistic role remains unclear. 8:2 fluorotelomer alcohol (8:2 FTOH), a per- and polyfluoroalkyl substance compound, was identified as an exogenous ligand for AHR. We demonstrate that AHR ligands drive mitochondrial outer membrane permeabilization (MOMP) and mitochondrial permeability transition (MPT) via transcriptional and non-transcriptional activation of AHR, promoting mitochondrial DNA (mtDNA) leakage and AIM2 inflammasome activation-the key mechanism of 8:2 FTOH-induced inflammation. Mechanistically, the F1F0ATP synthase/ATPase activity inhibition and B-cell lymphoma-2 (BCL-2)-associated X and BCL-2 antagonist/killer expression increase, with crosstalk between MOMP and MPT amplifying the mtDNA release. Inhibition of AHR/AIM2 alleviates the 8:2 FTOH-caused inflammation. Our findings establish AHR as a central regulator of mitochondrial DAMP signaling, and we propose therapeutic strategies for inflammatory diseases linked to environmental AHR activation.
    Keywords:  AHR; AIM2 inflammasome; CP: Immunology; MOMP; MPT; inflammatory; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.celrep.2025.116673
  10. Front Immunol. 2025 ;16 1669054
    DAMP-driven trained immunity: metabolic and epigenetic reprogramming in critical illness and chronic inflammation.
    Han G Kim, Jaimar C Rincon, Philip A Efron, Robert Maile.
      Innate immune memory, traditionally underappreciated in contrast to adaptive immunity, is now recognized as a critical component of host defense, particularly in the context of sepsis and sterile inflammatory injury. Recent advances have identified a central role for metabolic and epigenetic reprogramming in driving trained immunity (TRIM), where monocytes, macrophages, and other innate cells develop enhanced or tolerized responses to secondary stimuli. This review synthesizes current knowledge of how damage-associated molecular patterns (DAMPs), including oxidized LDL, HMGB1, heme, urate crystals, and mitochondrial DNA, serve as potent inducers of immunometabolic rewiring, often through the mTOR/HIF-1α axis or alternative pathways such as SYK signaling. We highlight distinct epigenetic mechanisms, such as enhancer priming via H3K4me1/H3K27ac, and metabolic shifts like the Warburg effect, succinate accumulation, and fatty acid synthesis, that define the trained or tolerized states. Particular attention is given to the relevance of these mechanisms in the pathophysiology of sepsis, burns, trauma, and other critical illnesses where persistent DAMP exposure may sustain maladaptive inflammation or immunosuppression. We review data linking central (stem cell-level) and peripheral reprogramming to long-term immune dysfunction in various inflammatory disease models, and explore how DAMPs intersect with PAMPs to shape the immune trajectory. Finally, we identify pressing gaps in the field, including the need for standardized TRIM models, validated biomarkers of innate memory, and mechanistic clarity on mitochondrial DAMPs in immune tolerance. These insights provide a foundation for future therapeutic strategies aimed at modulating trained immunity to improve outcomes in critically ill patients.
    Keywords:  DAMPs; epigenetics; innate immunity; innate training; trauma
    DOI:  https://doi.org/10.3389/fimmu.2025.1669054
  11. Nat Commun. 2025 Dec 11.
    An antimicrobial daptide from human skin commensal Staphylococcus hominis protects against skin pathogens.
    Amber Nguyen, Zoie L Bunch, Ingrid Y Martinez-Aldino, Manuel Rangel-Grimaldo, Uday Tak, John C Thorstenson, Morgan M Severn, Teruaki Nakatsuji, Richard L Gallo, Tyler N Graf, Nicholas H Oberlies, Jonathan R Chekan, Nadja B Cech, Alexander R Horswill.
      Coagulase-negative staphylococci are dominant human skin colonizers, producing natural products that shape the community and prevent pathogen colonization. The molecular mechanisms by which these natural products mediate interbacterial competition are not fully understood. Here, we identify a plasmid-borne daptide bacteriocin (hominicin) from a human skin isolate of Staphylococcus hominis, which features an unusual N2-N2-dimethyl-1,2-propanediamine C-terminus. Heterologous expression of the reconstituted biosynthetic loci yields a daptide product of the same molecular mass that exhibits antimicrobial activity against the skin pathogen Staphylococcus aureus, with amino-modified termini being essential for activity. Membrane permeability and voltage-clamp lipid bilayer experiments support a mechanism by which the daptide rapidly dissipates the transmembrane potential by forming peptidic channels. Additionally, we identify a cognate homI gene that confers resistance against membrane damage. Finally, the purified daptide effectively protects mouse skin from S. aureus-induced epicutaneous injury, as evidenced by reduced bacterial burden, inflammation, and transepithelial water loss, highlighting its therapeutic potential for treating bacterial skin infections. Our findings elucidate a mechanism of action, biosynthesis, and resistance for a staphylococcal bacteriocin belonging to a class of natural products called daptides.
    DOI:  https://doi.org/10.1038/s41467-025-66259-w
  12. J Exp Med. 2026 Feb 02. pii: e20250240. [Epub ahead of print]223(2):
    A circadian checkpoint relocates neutrophils to minimize injury.
    Alejandra Aroca-Crevillén, Sandra Martín-Salamanca, Lidiane S Torres, Georgiana Crainiciuc, Jon Sicilia, Eduardo Peñaloza-Martínez, Nicolás Rosillo, Miguel Molina-Moreno, Jose M Adrover, Andrea Rubio-Ponce, Tommaso Vicanolo, Xiaosong Liu, Kanin Wichapong, Vanessa Núñez, Karl Balabanian, Françoise Bachelerie, David Sancho, María Casanova-Acebes, José T Ortiz-Pérez, María Ángeles Moro, Héctor Bueno, Gerry A F Nicolaes, Andrés Hidalgo.
      Inflammation-driven injury, a significant source of morbidity and mortality worldwide, is largely mediated by the cytotoxic activities of neutrophils, which extend the initial lesion and jeopardize organ function. Intriguingly, inflammatory injury naturally declines at specific times of day, suggesting that circadian mechanisms exist that mitigate the destructive activity of neutrophils and protect the host. Here, we show that the periods of diurnal protection coincide with peaks in plasma CXCL12, a chemokine that inhibits the neutrophil-intrinsic circadian clock by signaling through CXCR4. Genetic deletion of this clock, or a hyperactive form of CXCR4, prevented the diurnal spikes of injury, and treatment with a synthetic CXCR4 agonist conferred protection from myocardial and vascular injury. In tissues, this protection was mediated by repositioning neutrophils in the wound core, which spared neighboring host cells from apoptotic death. Thus, a circadian neutrophil checkpoint protects from exuberant inflammation and can be activated to protect the host.
    DOI:  https://doi.org/10.1084/jem.20250240
  13. Cell Death Differ. 2025 Dec 09.
    NEDD 4 Pyre-fighters to extinguish inflammation: NEDD4L ubiquitinates Gasdermin D and Gasdermin E to dampen pyroptosis.
    Kailash Gulshan.
      
    DOI:  https://doi.org/10.1038/s41418-025-01626-0
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