bims-cediti 2026-08-02 papers

bims-cediti

Biomed News

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

Issue of 2026–08–02
twelve papers selected by
Kateryna Shkarina, Universität Bonn

Systematic genetic analysis of GSDMD, GSDME, and MLKL activation and execution of PANoptosis.
NAD+ depletion links metabolic stress to drive innate immune priming and selectively control PANoptosis.
IFN-α and IFN-β inhibit NLRP1-driven PANoptosis.
Igniting antitumour immunity with cancer cell pyroptosis.
The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages.
PLCd4 signaling-mediated PI4P synthesis drives macrophage NLRP3 inflammasome activation to promote heat stroke-induced tissue injury.
Mitochondrial metabolism and epigenetic crosstalk drive SASP.
Ruptosis: a novel hormone-triggered cytotoxic cell death program linking endocrine homeostasis to innate immunity.
Non-canonical TLR signaling restricts cytosolic LPS detection.
Protocol to study inflammasome activation in induced pluripotent stem cell-derived macrophages.
Cell-autonomous immunity as an integrated immune network against bacterial and viral pathogens.
NEK7 accelerates NLRP3 inflammasome activation.

J Biol Chem. 2026 Jul 28. pii: S0021-9258(26)02242-8. [Epub ahead of print] 113370

Systematic genetic analysis of GSDMD, GSDME, and MLKL activation and execution of PANoptosis.

Omkar Indari, Prashant Giri, Rebecca E Tweedell, Thirumala-Devi Kanneganti.

  Cell death is a key effector mechanism of the innate immune system for host defense. While it is beneficial for pathogen clearance, excess lytic cell death is linked to inflammation, pathology, and disease. Therefore, tight regulation of cell death execution is critical. PANoptosis is an innate immune, lytic, and inflammatory cell death pathway initiated by innate immune sensors and driven by caspases and RIPKs, with roles in infection, inflammatory disease, and cancer. During PANoptosis, caspases and RIPKs within PANoptosome complexes activate multiple executioner proteins, including gasdermin (GSDM) family proteins and mixed lineage kinase domain-like pseudokinase (MLKL). These executioners form membrane pores that lead to membrane lysis and the release of DAMPs and cytokines. Although multiple executioners are activated during PANoptosis, the requirement for individual executioners in driving the lytic cell death remains unclear. To address this, we performed a comprehensive genetic analysis of GSDMD, GSDME, and MLKL using single, double, and triple knockout primary macrophages across triggers known to activate distinct PANoptosomes. Deletion of individual executioners did not reduce the activation of caspases or other executioners and did not fully block PANoptosis, suggesting these executioner molecules often act in a compensatory manner to execute PANoptosis. Furthermore, combined deletion of all three executioners provided greater protection than any single or double deletion. However, residual cell death still occurred even after genetic deletion of all three executioner proteins, suggesting the involvement of additional executioners that remain to be identified. Overall, our study suggests that targeting individual executioners will not be sufficient in disease contexts where PANoptosis drives pathology, and targeting the full executioner network or upstream molecules, such as sensors or essential PANoptosome complex components, will be needed for therapeutic efficacy in infection, inflammatory disease, and cancer.

Keywords:  AIM2; GSDMD; GSDME; MLKL; NLR; NLRC5; NLRP12; NLRP3; PANoptosis; PANoptosome; RIPK1; RIPK3; ZBP1; caspase; caspase-1; caspase-8; cell death; executioner; gasdermin; inflammasome; innate immunity

DOI:  https://doi.org/10.1016/j.jbc.2026.113370
J Immunol. 2026 Jul 10. pii: vkag203. [Epub ahead of print]215(7):

NAD+ depletion links metabolic stress to drive innate immune priming and selectively control PANoptosis.

Roman Sarkar, Nagakannan Pandian, Balamurugan Sundaram, Bhesh Raj Sharma, Peter A Gorsuch, Rebecca E Tweedell, Thirumala-Devi Kanneganti.

  The innate immune system can detect infection, tissue damage, and other homeostatic disruptions to initiate an immune response, drive inflammation, and promote programmed cell death. While these responses can be beneficial in host defense, aberrant activation of inflammatory, lytic cell death pathways can be pathogenic. Emerging evidence suggests that cellular metabolic disruption can promote inflammatory cell death, but the mechanistic connections between these processes are not well understood, limiting our ability to identify regulatory nodes that can be therapeutically targeted. Here, we found that intracellular levels of the metabolic cofactor nicotinamide adenine dinucleotide (NAD+) were depleted in response to cell death triggers that drive pyroptosis, necroptosis, PANoptosis, and ferroptosis. However, restoring NAD+ inhibited PANoptosis but not the other forms of cell death. Mechanistically, NAD+ restoration reduced the expression of PANoptotic sensors or regulators, including the transcription factor IRF1, a critical factor for innate immune sensor priming in PANoptosis. Our findings thereby suggest that NAD+ depletion is an early cell death signaling event and that restoring NAD+ levels specifically blocks PANoptosis by suppressing priming. Hence, targeting NAD+ metabolism represents a potential therapeutic strategy for infectious and inflammatory diseases associated with dysregulated PANoptosis.

Keywords:  AIM2; NLRC5; NLRP12; NLRP3; ZBP1

DOI:  https://doi.org/10.1093/jimmun/vkag203
EMBO Rep. 2026 Jul 29.

IFN-α and IFN-β inhibit NLRP1-driven PANoptosis.

Bhesh Raj Sharma, Harisankeerth Mummareddy, Sangappa B Chadchan, Roman Sarkar, Chadi A Ei Farran, Thirumala-Devi Kanneganti.

Pathogens, tissue damage, and cellular stress are detected by innate immune sensor molecules to drive inflammatory signaling and cell death. Mutations in the sensor NLRP1 are associated with inflammatory disease, but the regulation of this sensor is not well understood. Here, we find that LPS, a TLR4 ligand and canonical activator of innate immunity, inhibits NLRP1-mediated caspase activation, IL-18 release, and inflammatory cell death, PANoptosis. This inhibition requires TRIF but not MyD88, implicating TRIF-dependent TLR signaling. IRF3 is also required, suggesting an essential role for type I IFN signaling. Indeed, IFN-β production or treatment with exogenous IFN-α or IFN-β inhibits NLRP1-dependent PANoptosis in mouse bone marrow-derived macrophages and human macrophages and monocytes. Mechanistically, Nlrp1b/NLRP1 expression is significantly reduced in LPS- or type I IFN-treated cells. Overall, our study identifies a TLR4-TRIF-IRF3 signaling axis that induces type I IFNs to negatively regulate NLRP1 transcription, thereby blocking NLRP1-driven, caspase-1/caspase-8/RIPK3-dependent PANoptosis. These findings suggest type I IFNs as a potential therapeutic strategy for NLRP1-driven inflammatory diseases.

DOI: https://doi.org/10.1038/s44319-026-00888-0
Nat Rev Cancer. 2026 Jul 27.

Igniting antitumour immunity with cancer cell pyroptosis.

Xin Liu, Elena Goldberg, Jonathan C Kagan, Hao Wu.

Gasdermins (GSDMs) are a family of pore-forming proteins that execute pyroptosis, a lytic form of programmed cell death associated with membrane rupture. This function of GSDMs was initially identified from studies of gasdermin D (GSDMD), which is cleaved and activated by inflammatory caspases in the inflammasome pathway. It is now established that other eukaryotic or pathogen-encoded proteases, as well as post-translational modifications, can also activate GSDM family members independent of inflammasomes and in multiple cell types including cancer cells. T cell granzyme-mediated GSDM activation, exogenous delivery of active GSDMs, and small molecule-induced activation of GSDMs in cancer cells have been shown to promote antitumour immunity through pyroptosis. Notably, only a fraction of cancer cells needs to undergo pyroptosis to induce immune cell infiltration and antitumour immunity with tolerable toxicity. Here, we summarize current knowledge on the role of pyroptosis in antitumour immunity, discuss pyroptosis in the context of other lytic forms of cell death, and provide an outlook on how cancer cell pyroptosis may synergize with existing immunotherapies.

DOI: https://doi.org/10.1038/s41568-026-00959-3
J Cell Sci. 2026 Jul 15. pii: jcs265083. [Epub ahead of print]139(14):

The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages.

Rebecca Morrison, Simeon R Mihaylov, Chak Hon Luk, Cyril Lemerle, Angela Rodgers, Natalia Athanasiadi, Huw R Morris, Enrica Pellegrino, Sila K Ultanir, Maximiliano G Gutierrez.

  Variants in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, yet how these variants alter immune cell function remains unclear. Because LRRK2 is activated by lysosomal damage in macrophages, we investigated how the pathogenic G2019S variant affects macrophage responses to lysosomal damage. Here, we show that LRRK2 G2019S has an effect during lysosomal damage through kinase-dependent and kinase-independent mechanisms. Phosphoproteomic analysis revealed that lysosomal damage induces selective rewiring of LRRK2-dependent Rab GTPase phosphorylation, characterised by increased Rab12 phosphorylation and reduced Rab35 phosphorylation without global kinase hyperactivation. Strikingly, LRRK2 G2019S macrophages showed increased susceptibility to apoptosis following lysosomal damage. This increase in cell death occurred independently of the kinase activity, indicating a distinct kinase-independent role of LRRK2 in regulating cell survival. We generated isogenic induced pluripotent stem cells from patients carrying the LRRK2 G2019S variant and confirmed that LRRK2 G2019S macrophages are more susceptible to cell death in a kinase-independent manner. Together, our findings support a model in which the LRRK2 G2019S variant selectively changes the phosphorylation of Rab GTPases in macrophages and increases cell death after lysosomal damage in macrophages.

Keywords:  Apoptosis; LRRK2; Lysosomal damage; Macrophage; Parkinson's disease; Rab GTPase

DOI:  https://doi.org/10.1242/jcs.265083
Cell Rep. 2026 Jul 30. pii: S2211-1247(26)00779-5. [Epub ahead of print]45(8): 117701

PLCd4 signaling-mediated PI4P synthesis drives macrophage NLRP3 inflammasome activation to promote heat stroke-induced tissue injury.

Riqing Wei, Wenqian Zheng, Chenxin Liu, Dinghao Dang, Xinyu Deng, Xiaoting Hu, Hui Liang, Xi Luo, Jiayi Tang, Wei Zhu, Shuogui Xu, Ru Li, Qiang Ma.

  Heat stroke causes life-threatening systemic inflammation and multiorgan injury, but the intracellular mechanisms that sustain inflammatory amplification after heat exposure remain unclear. Here, using heat stroke mouse models, genetic NLRP3 deletion, pharmacological inhibition, myeloid-specific NLRP3 deficiency, macrophage depletion, and heat-stressed macrophage systems, we show that tissue macrophage NLRP3 inflammasome activation is a central driver of interleukin-1β/interleukin-18 release, organ injury, and mortality. Mechanistically, heat stroke enhances phospholipase C delta 4 signaling, promotes diacylglycerol accumulation at trans-Golgi network/Golgi-associated membranes, recruits protein kinase D1, and increases phosphatidylinositol 4-kinase β-dependent phosphatidylinositol 4-phosphate production. This lipid remodeling supports NLRP3 recruitment, ASC speck formation, caspase-1 activation, and inflammatory cytokine release. Phospholipase C delta 4 knockdown preferentially suppresses NLRP3 activation induced by heat stroke, but not by canonical stimuli. These findings link heat stroke to membrane lipid remodeling and spatial inflammasome assembly, identifying a potential organ-protective pathway in heat stroke.

Keywords:  CP: immunology; CP: metabolism; NLRP3 inflammasome; PI4KB; PI4P; PLCd4; heat stroke; macrophages; multiorgan injury

DOI:  https://doi.org/10.1016/j.celrep.2026.117701
Nature. 2026 Jul 29.

Mitochondrial metabolism and epigenetic crosstalk drive SASP.

Hélène Martini, Jodie Birch, Francisco D M Marques, Stella Victorelli, Anthony B Lagnado, Nicholas Pirius, Ana Catarina Franco, Gung Lee, Yeaeun Han, Jennifer L Rowsey, Wazim Mohammed Ismail, Amelia Mazzone, Tianna M Espe, Taro Hitosugi, Ya Li, Alexander M Washington, Aaron Havas, Rabi Murad, Xue Lei, Rebecca A Porritt, Oliver D K Maddocks, Jair Machado Espindola-Netto, Dominik Saul, Sundeep Khosla, Diana Jurk, Enis Kostallari, Alexandre Gaspar-Maia, Peter D Adams, João F Passos.

Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP)1. Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme2,3. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes. Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.

DOI: https://doi.org/10.1038/s41586-026-10791-2
Apoptosis. 2026 Jul 31. pii: 201. [Epub ahead of print]31(8):

Ruptosis: a novel hormone-triggered cytotoxic cell death program linking endocrine homeostasis to innate immunity.

Feng Tang.

A landmark 2026 Cell publication by Chai et al. characterized Ruptosis, a previously unclassified form of regulated cell death executed by specialized glandular immune cells termed ruptoblasts in the planarian Schmidtea mediterranea. Triggered exclusively by elevated activin (a dual hormone/inflammatory cytokine), Ruptosis manifests rapid, contact-independent explosive cellular disintegration and releases diffusible toxins to eliminate aberrant somatic cells, stem cells and invading bacteria. Distinct from apoptosis, pyroptosis, necroptosis, ferroptosis and neutrophil NETosis at morphological, biochemical and kinetic levels, this novel lytic pathway substantially expands the canonical regulated cell death (RCD) classification system. This commentary outlines the defining unique features of Ruptosis and discusses its evolutionary implications for cell death and innate immunity research.

DOI: https://doi.org/10.1007/s10495-026-02414-y
bioRxiv. 2026 Jul 13. pii: 2025.03.10.642106. [Epub ahead of print]

Non-canonical TLR signaling restricts cytosolic LPS detection.

Shriram Ramani, Sara Cahill, Matthew Finnegan, Laurel Stine, Abigail Sondrini, Kiera Clayton, Liraz Shmeul-Galia, Fiachra Humphries.

Intracellular sensing of lipopolysaccharide (LPS) is an essential component of pathogen detection that governs the innate immune response. However, how this process is controlled to maintain homeostasis and resolve inflammation is unclear. Here, we show that MARCO is a decoy LPS sensor crucial for restraining caspase 11 activity and the non-canonical inflammasome. Remarkably, MARCO expression is controlled by a non-canonical TLR signaling pathway involving the metabolite itaconate, the autophagy adaptor protein p62, and the transcription factor NRF2. In the presence of IFN, non-canonical TLR signaling is impaired and NRF2 dependent gene expression is terminated. Thus, impairing MARCO expression and licensing optimal activation of the non-canonical inflammasome. Loss of MARCO augments non-canonical inflammasome activation and sensitizes mice to septic shock. Together, this study identifies MARCO as a previously unknown LPS sensor that is regulated by a non-canonical TLR signaling pathway and reveals an intricate homeostatic switch that allows for optimal immune responses and resolution of inflammation.

DOI: https://doi.org/10.1101/2025.03.10.642106
STAR Protoc. 2026 Jul 28. pii: S2666-1667(26)00400-4. [Epub ahead of print]7(3): 104747

Protocol to study inflammasome activation in induced pluripotent stem cell-derived macrophages.

Chloe M McKee, Melanie Cranston, Emma C McKay, Mohammad Arefian, Ben C Collins, Rebecca C Coll.

  Macrophages are widely used to study inflammasome activity, but current in vitro macrophage models have various limitations. Here, we describe a protocol to differentiate induced pluripotent stem cell (iPSC)-derived macrophages (iMacs) and to characterize these cells via flow cytometry, phagocytosis assays, and whole-cell proteomics. We then describe how to activate a range of different inflammasomes within these cells and assess the inflammasome response through measurement of pyroptosis, cytokine release, ASC speck formation, and protein processing via western blotting. For complete details on the use and execution of this protocol, please refer to McKee et al.1.

Keywords:  Cell Differentiation; Cell culture; Flow Cytometry; Immunology; Mass Spectrometry; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2026.104747
Nat Microbiol. 2026 Aug;11(8): 2098-2111

Cell-autonomous immunity as an integrated immune network against bacterial and viral pathogens.

Lorena Martín-González, Bruno Ramos, Yizhou Huang, Teresa Thurston, Greg Towers, Damián Lobato-Márquez.

All cells possess a diverse array of cell-autonomous immune responses that can detect and restrict infections by intracellular pathogens. These intrinsic responses (both passive and active) enable individual cells to autonomously block bacterial and viral invasion and replication. Epithelial and endothelial cells act as a first line of defence, coordinating immune responses that preserve host barrier integrity. These cells can also mount specialized innate immune responses (many of which are triggered by antimicrobial cytokines, such as interferons) to limit the replication and motility of intracellular bacteria and viruses. To counteract these, bacteria and viruses have developed strategies to avoid or antagonize host defences, driving an evolutionary arms race that shapes every aspect of host-pathogen interactions. This Review provides an overview of current knowledge of cell-autonomous immunity against bacteria and viruses. We emphasize the factors underpinning host cell surveillance and restriction of cytosolic pathogens and mechanisms of immune evasion deployed by the invading microorganism.

DOI: https://doi.org/10.1038/s41564-026-02428-x
J Mol Biol. 2026 Jul 29. pii: S0022-2836(26)00333-5. [Epub ahead of print] 169960

NEK7 accelerates NLRP3 inflammasome activation.

Svenja Wöhrle, Tamara Ćiković, Clara Dufossez, Emilia Neuwirt, Elena Puma, Franziska Kraatz, Anna Kostina, Oliver Gorka, Clemens Kreutz, Christina J Groß, Olaf Groß.

  The NLRP3 inflammasome is a major driver of immunopathology, making it a sought-after drug target. In spite of two decades of intense research, its activation mechanism is still poorly understood, impeding inhibitor design. NEK7 was reported to be essential for NLRP3 activation, and several newly identified NLRP3 inhibitors were suggested to act by interfering with their interaction. Here we report that NEK7 accelerates, but is in principle dispensable for NLRP3 activation. The onset of inflammasome activation on the single-cell level was unaltered in the absence of NEK7, yet the rate of cells to undergo inflammasome formation and subsequent pyroptosis was approximately 4-fold reduced. Therefore, therapeutic targeting of the NEK7-NLRP3 interaction might have an incomplete effect, which has to be considered for drug development. We confirmed entrectinib as a NEK7-dependent inhibitor, while other published drug candidates turned out not to rely on its presence. Our results support two possible scenarios for the role of NEK7 in NLRP3 activation: either, NEK7 accelerates one unique pathway of NLRP3 activation, or it is essential for a first, fast pathway, while being dispensable for a second, slower NLRP3 activation pathway.

Keywords:  Inflammasome; NEK7; NLRP3

DOI:  https://doi.org/10.1016/j.jmb.2026.169960