bims-cediti 2025-07-13 papers

bims-cediti

Biomed News

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

Issue of 2025–07–13
eight papers selected by
Kateryna Shkarina, Universität Bonn

Crosstalk Between ALPK1 and STING: A Synergistic Axis in Innate Immune Activation and Human Inflammatory Disease.
Pattern Recognition by NOD-Like Receptors.
The brain-derived neurotrophic factor mimetic 7,8-dihydroxyflavone mitigates NLRP3 inflammasome activation and GSDMD-mediated pyroptosis and enhances the negative regulatory pathways of pyroptosis in microglia.
NLRP3 inflammasome-driven hemophagocytic lymphohistiocytosis occurs independent of IL-1β and IL-18 and is targetable by BET inhibitors.
A cereblon-based glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner.
Cytoskeleton disruption and plasma membrane damage determine methuosis of normal and malignant cells.
A noncanonical cGAS-STING pathway drives cellular and organismal aging.
Thapsigargin triggers a non-apoptotic, caspase-independent programmed cell death in basophilic leukaemia cells.

bioRxiv. 2025 Jul 04. pii: 2025.06.30.662363. [Epub ahead of print]

Crosstalk Between ALPK1 and STING: A Synergistic Axis in Innate Immune Activation and Human Inflammatory Disease.

Chong-Shan Shi, Christina Kozycki, Ning-Na Huang, Il-Young Hwang, Dima A Hammoud, Daniel L Kastner, John H Kehrl.

Alpha kinase 1 (ALPK1) is a cytosolic sensor of microbial sugar metabolites that activates NF-κB signaling through phosphorylation of the adaptor protein TIFA. Although canonically linked to NF-κB, individuals with gain-of-function ALPK1 mutations also show features of interferon-driven inflammation. Here, we show that ALPK1 activation enhances multiple outputs of the stimulator of interferon genes (STING) pathway, including both canonical and noncanonical responses such as STING proton channel-dependent LC3B lipidation and NLRP3 inflammasome activation. Furthermore, ALPK1 signaling activates eIF2α, an effector of the integrated stress response. Conversely, STING activation increases ALPK1 protein expression and triggers TIFA-Threonine 9 phosphorylation. Clinically, individuals with ALPK1-mediated disease exhibit premature intracranial mineralization and elevated cerebrospinal fluid neopterin, both associated with dysregulated interferon signaling. These findings support a model of bidirectional signaling between ALPK1 and STING, in which microbial and nucleic acid sensing pathways can amplify one another. This crosstalk provides a mechanistic framework for understanding innate immune signaling relevant to both homeostasis and disease.

DOI: https://doi.org/10.1101/2025.06.30.662363
Adv Exp Med Biol. 2025 ;1476 83-105

Pattern Recognition by NOD-Like Receptors.

Timo-Daniel Voss, Lucy Hezinger, Thomas A Kufer.

  Nucleotide-binding oligomerization domain-like receptors (NLRs) are a family of cytosolic pattern recognition receptors (PRRs) and able to respond to conserved microbe-associated molecular patterns (MAMPs) and endogenous damage-associated molecular patterns (DAMPs). NLRs modulate the inflammatory response via multiple pathways including nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB)-activation, mitogen-activated protein kinase (MAPK)-pathways and both canonical and non-canonical inflammasome formation. The latter results in auto-processing of caspase-1 and subsequent maturation of the cytokines interleukin 1 beta (IL-1β) and IL-18 as well as induction of pyroptosis by cleavage of gasdermin D (GSDMD) that induces pores in the cell membrane. NLRs act in synergy with other PRRs but some NLRs directly modulate adaptive immunity via transcriptional regulation of major histocompatibility complex (MHC) class I and class II. NLRs have an essential role as intracellular PRRs and thereby orchestrate inflammatory responses. NLR mutations and subsequent dysfunction can result in cancer or autoinflammatory diseases, such as Crohn's disease and ulcerative colitis, and many more, indicating their important role in classical immune recognition, maintenance of tissue homeostasis and reproductive functions. Here, we discuss our current understanding of mammalian NLRs that act as PRRs.

Keywords:  DAMP; Damage-associated molecular patterns; MAMP; Microbe-associated molecular patterns; NLR; NOD-like receptors; PRR; Pattern recognition receptors

DOI:  https://doi.org/10.1007/978-3-031-85340-1_4
J Neuroimmunol. 2025 Jul 05. pii: S0165-5728(25)00165-1. [Epub ahead of print]406 578684

The brain-derived neurotrophic factor mimetic 7,8-dihydroxyflavone mitigates NLRP3 inflammasome activation and GSDMD-mediated pyroptosis and enhances the negative regulatory pathways of pyroptosis in microglia.

Mehmet Erdem, Şeniz Erdem, Süleyman Caner Karahan, Ahmet Alver, Soner Karabulut, Gökhan Yıldız.

  Microglia are resident immune cells of brain, which serves as a driver of the innate immunity within the central nervous system (CNS). The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that is critical component of the innate immunity and hyperactivation of inflammasome under various conditions contributing to the pathogenesis of neurodegenerative diseases (NDs). 7,8-Dihydroxyflavone (7,8-DHF) have become the focus of attention in studies on NDs due to exert its neurotrophic effects in the CNS. Recent studies have shown encouraging outcomes targeting immune regulatory and neuroprotective properties. 7,8-DHF is a specific tropomyosin-related kinase receptor B (TrkB) agonist and bioavailable brain-derived neurotrophic factor (BDNF) mimetic, which has immunomodulator properties in the CNS. In the present study, we researched the effects of BDNF mimetic 7,8-DHF on NLRP3 inflammasome activation, GSDMD-mediated pyroptosis, NF-κB signaling, ESCRT-III-dependent plasma membrane repair, and selective autophagy in LPS plus ATP-induced murine N9 microglial cells. These findings demonstrated that BDNF mimetic 7,8-DHF significantly reduced NLRP3 inflammasome activation, decreased active caspase-1 the levels, inhibited secretion of proinflammatory cytokine IL-1β and IL-18 levels through the IκBα/NF-κB axis. Furthermore, we showed that BDNF mimetic 7,8-DHF activated selective autophagy and ESCRT-III-dependent plasma membrane repair, both of which play crucial roles in the negative regulation of NLRP3 inflammasome activation. Our study reveals that BDNF mimetic 7,8-DHF effectively prevents microglial NLRP3 inflammasome activation and GSDMD-mediated pyroptosis by inhibiting IκBα/NF-κB, promoting ESCRT-III-dependent plasma membrane repair and enhancing selective autophagy.

Keywords:  7,8-dihydroxyflavone; ESCRT-III-dependent plasma membrane repair; Microglia; NLRP3 inflammasome; Pyroptosis; Selective autophagy

DOI:  https://doi.org/10.1016/j.jneuroim.2025.578684
Sci Adv. 2025 Jul 11. 11(28): eadv0079

NLRP3 inflammasome-driven hemophagocytic lymphohistiocytosis occurs independent of IL-1β and IL-18 and is targetable by BET inhibitors.

Farzaneh Shojaee, Esmaeel Azadian, Min Xian Wong, Xiuquan Ma, James Rickard, Jiyi Pang, Catherine Hall, Andrew J Kueh, Seth L Masters, Inmaculada Rioja, Rab K Prinjha, Marcel Doerflinger, Kate E Lawlor, Maryam Rashidi, James E Vince.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal cytokine storm syndrome. Its high mortality rate reflects limited therapeutic options and a poor understanding of disease-causing signaling. We show that the NLRP3 inflammasome is responsible for increased mortality in a model of secondary HLH (sHLH). Unexpectedly, neither deletion of the NLRP3-activated pyroptotic effector GSDMD nor combined deletion of the inflammasome-activated cytokines interleukin-1β (IL-1β) and IL-18 conferred strong protection from sHLH. Instead, co-deletion of GSDMD and caspase-8-activated GSDME limited sHLH-driven lethality, demonstrating redundancy in the pyroptotic machinery required to induce sHLH. We also found that bromodomain and extraterminal domain (BET) inhibitors prevent NLRP3-driven pyroptosis, which acted by blocking inflammasome priming. BET inhibitors prevented increased NLRP3 levels in diseased tissue, limited the production of sHLH-associated IL-1β, interferon-γ, and tumor necrosis factor, and protected from sHLH pathogenesis. These findings suggest that targeting NLRP3 could limit sHLH and identify clinically relevant bromodomain-selective BET inhibitors capable of eliminating NLRP3-driven pyroptosis and the sHLH cytokine storm.

DOI: https://doi.org/10.1126/sciadv.adv0079
Cell Chem Biol. 2025 Jul 07. pii: S2451-9456(25)00200-4. [Epub ahead of print]

A cereblon-based glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner.

Aude Sylvain, Natacha Stoehr, Fupeng Ma, Artiom Cernijenko, Martin Schröder, Maryam Khoshouei, Melanie Vogelsanger, Michel Schoenboerner, Ashley Burke, Pasupuleti Rao, Jonathan M Solomon, Joshiawa Paulk, Lei Xu, Janet Dawson, Damien Begue, Peggy Lefeuvre, Erik Ahrne, Andreas Hofmann, Callum J Dickson, Philip Arabin, Alfred Zimmerlin, Michael Kiffe, Mirjam Froehlicher, Theresa Boersig, Azeddine Elhajouji, Murielle Brichet, Suchithra Menon, Shanming Liu, Matthias Mueller, Charles A Wartchow, James Lin, Yamel Cardona Gloria, Sabine Dickhöfer, Alexander N R Weber, Tatjana Welzel, Jasmin Kuemmerle-Deschner, Christopher J Farady, Robert Pulz, Frederic Bornancin, Dennis L Buckley, Zuni I Bassi.

  Aberrant NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome activation is linked to many inflammatory diseases, driving the search for therapeutics inhibiting this pathway. NEK7 is proposed to mediate NLRP3 inflammasome assembly and activation by bridging adjacent NLRP3 subunits. Hence, reduction of NEK7 protein may block NLRP3 activation. We identified NK7-902, a potent and selective cereblon (CRBN) glue degrader of NEK7. NK7-902 degraded NEK7 in human immune cells and whole blood. However, full NEK7 degradation completely blocked NLRP3-dependent interleukin-1β (IL-1β) release in vitro only in certain donors and experimental conditions. Unlike most CRBN glue degraders, NK7-902 effectively degraded NEK7 in murine cells and inhibited IL-1β release in mouse in vivo. By contrast, oral administration of NK7-902 in cynomolgus monkey caused long-lasting NEK7 degradation but only transiently blocked IL-1β in blood. These findings suggest NEK7 contributes to but is not absolutely required for NLRP3 activation in monkeys and humans.

Keywords:  CRBN; NEK7; NLRP3 inflammasome; inflammation; molecular glue degrader

DOI:  https://doi.org/10.1016/j.chembiol.2025.06.005
Cell Biosci. 2025 Jul 05. 15(1): 96

Cytoskeleton disruption and plasma membrane damage determine methuosis of normal and malignant cells.

Bin Dong, Jing Xiao, Junqi Wang, Xinhao Song, Hui Ji, Jiurong Peng, Xinru Weng, Dawei Guo, Shanxiang Jiang, Xiuge Gao.

BACKGROUND: Methuosis represents a novel cell death modality characterized by catastrophic cytoplasmic vacuolization in normal and malignant cells. However, the critical role and the underlying mechanism of cytoskeleton and plasma membrane damage in methuotic cells are largely unknown.
RESULTS: We found that cytoskeleton protein F-actin, α-tubulin, β-tubulin and filamin A/B were disrupted in a reversible-dependent manner. In addition, RhoA-ROCK1 signaling pathway mediated cytoskeleton disruption in methuotic cells. Excessive cytoplasmic vacuolization triggered cellular plasma membrane damage and the release of damage associated molecular patterns (DAMPs), including lactate dehydrogenase (LDH), adenosine triphosphate (ATP) and calreticulin (CRT). Furthermore, at the end phase of methuotic cells, plasma membrane was damaged independent of pore-forming protein phosphorylation mixed lineage kinase domain-like (p-MLKL) and gasdermin D (GSDMD). Endosomal sorting complex required for transport (ESCRT)-III especially its subunit charged multivesicular body protein 3 (CHMP3) and charged multivesicular body protein 5 (CHMP5) negatively regulated excessive vacuolization-induced plasma membrane damage in cells undergoing methuosis.
CONCLUSIONS: The critical role and potential mechanism of cytoskeleton and plasma membrane damage in methuotic cells are known, which would facilitate the employment of methuosis in life science and pharmacology.

DOI: https://doi.org/10.1186/s13578-025-01441-7
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2424666122

A noncanonical cGAS-STING pathway drives cellular and organismal aging.

Rafael Cancado de Faria, Lilian N D Silva, Barbara Teodoro-Castro, Kyle S McCommis, Elena V Shashkova, Susana Gonzalo.

  Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. Stimulator of interferon genes (STING) protein translates the sensing of cytosolic DNA by cyclic-GMP-AMP synthase (cGAS) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS-STING pathway leads to aging remain poorly understood. We show that STING does not follow the canonical pathway of activation in human fibroblasts passaged (aging) in culture, senescent fibroblasts, or progeria fibroblasts (from Hutchinson-Gilford progeria syndrome patients). Despite cytosolic DNA buildup, features of the canonical cGAS-STING pathway like increased cGAMP production, STING phosphorylation, and STING trafficking to perinuclear compartment are not observed in progeria/senescent/aging fibroblasts. Instead, STING localizes at endoplasmic reticulum, nuclear envelope, and chromatin. Despite the nonconventional STING behavior, aging/senescent/progeria cells activate inflammatory programs such as the senescence-associated secretory phenotype and the interferon response, in a cGAS and STING-dependent manner, revealing a noncanonical pathway in aging. Importantly, progeria/aging/senescent cells are hindered in their ability to activate the canonical cGAS-STING pathway with synthetic DNA, compared to young cells. This deficiency is rescued by activating vitamin D receptor signaling, unveiling mechanisms regulating the cGAS-STING pathway in aging. Significantly, in HGPS, inhibition of the noncanonical cGAS-STING pathway ameliorates cellular hallmarks of aging, reduces tissue degeneration, and extends the lifespan of progeria mice. Our study reveals that a new feature of aging is the progressively reduced ability to activate the canonical cGAS-STING pathway in response to cytosolic DNA, triggering instead a noncanonical pathway that drives senescence/aging phenotypes.

Keywords:  aging; cGAS; cytosolic DNA; senescence-associated secretory phenotype; stimulator of interferon genes

DOI:  https://doi.org/10.1073/pnas.2424666122
Cell Death Discov. 2025 Jul 08. 11(1): 313

Thapsigargin triggers a non-apoptotic, caspase-independent programmed cell death in basophilic leukaemia cells.

Philip Steiner, Korollus Melek, Ancuela Andosch, Lena Wiesbauer, Anna Madlmayr, Michelle Duggan, Hubert H Kerschbaum, Susanna Zierler.

Thapsigargin (TG), a potent inhibitor of the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), is widely used to study intracellular Ca²⁺ homeostasis and has shown-along prodrug derivatives-promise as an anticancer agent. While TG is traditionally considered an inducer of apoptosis, the precise mode of cell death it triggers remains incompletely defined. Here, we investigated the effects of TG on rat basophilic leukaemia (RBL-1) cells using advanced 2D and 3D transmission electron microscopy, confocal laser scanning microscopy, and functional cell death assays. TG treatment led to marked ultrastructural alterations, including pronounced ballooning of the perinuclear space, extensive vacuolization, mitochondrial enlargement and degradation, and structural anomalies of the endoplasmic reticulum. Notably, classical apoptotic features such as nuclear fragmentation, chromatin condensation and apoptotic body formation were absent. Functional assays revealed minimal caspase-3/7 activation and low Annexin V staining, indicating a caspase-independent, non-apoptotic form of programmed cell death (PCD). Morphological and quantitative analyses demonstrated that TG-induced cell death in RBL-1 cells closely resembles autosis, a non-apoptotic, autophagy-dependent PCD characterized by perinuclear space ballooning and increased autophagolysosome formation. These autosis-like features were also observed in TG-treated murine macrophages and human mast cells, suggesting a conserved mechanism across cell types. Digoxin, a Na⁺/K⁺-ATPase inhibitor, partially reversed TG-induced ultrastructural damage, supporting the involvement of Na⁺/K⁺-ATPase in this process. Ca²⁺ imaging confirmed that TG-induced cytosolic Ca²⁺ elevation is primarily driven by ER Ca²⁺ release, with extracellular Ca²⁺ amplifying the response. Our findings establish that TG induces a non-apoptotic, caspase-independent PCD matching autosis, challenging the prevailing view of TG as a classical apoptosis inducer. This insight has important implications for research on intracellular Ca2+ homeostasis as well as for the therapeutic exploitation of TG and its derivatives in targeting apoptosis-resistant cancer cells.

DOI: https://doi.org/10.1038/s41420-025-02602-w