bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–11–16
fourteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. Evasion of CARD8 activation during HIV-1 assembly.
  2. The Hippo Kinases MST1/2 Integrate Sterile and Infectious Signals to Regulate Macrophage Cell Death.
  3. SIGLEC12 mediates plasma membrane rupture during necroptotic cell death.
  4. Single-cell analysis reveals cell death as driver of NLRP3-mediated secretion of IL-1β in human monocytes.
  5. Impaired NLRP3 inflammasome signaling diverts pyroptotic to apoptotic caspase activation in macrophages.
  6. Non-apoptotic caspase-8 is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection.
  7. Post-translational modifications of NLRP3: to prime or not to prime?
  8. A glucose kinase-independent HK2 activity prevents TNF-induced cell death by phosphorylating RIPK1.
  9. AIM2 drives inflammatory cell death and monkeypox pathogenesis.
  10. The tumor suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis.
  11. Bacteria block host cell death by protein cut-and-paste.
  12. YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis.
  13. A Pseudomonas aeruginosa quorum-sensing metabolite manipulates macrophage ferroptosis through a methylation pathway.
  14. Histones present on the surface of late apoptotic cells induce RAGE-mediated phagocytosis.
  1. Sci Adv. 2025 Nov 14. 11(46): eadz1069
    Evasion of CARD8 activation during HIV-1 assembly.
    Ivy K Hughes, James B Hood, Andrés A Quiñones-Molina, Hisashi Akiyama, Suryaram Gummuluru.
      As intracellular parasites, viruses must devise sophisticated mechanisms to produce and assemble viral components while suppressing activation of innate immune effectors. Here, we report that coordination of HIV-1 assembly by the viral polyprotein Gag suppresses inappropriately timed protease (PR) activity to evade the PR activity sensor, caspase recruitment domain-containing protein 8 (CARD8). Using mutants of Gag, we show that disruption of domains controlling viral assembly site [matrix (MA)] or virus particle release (nucleocapsid and p6) leads to premature activation of PR and the CARD8 inflammasome, resulting in interleukin-1β (IL-1β) secretion and pyroptotic cell death. Further, we demonstrate that previously observed host-adaptive mutations in HIV-1 MA (M30K) and p6 (PTAP duplication) associated with greater fitness in humans improve infected CD4+ T cell survival in a PR-dependent manner, which may be regulated by CARD8. Together, this work reveals virus-encoded mechanistic control over PR activation and CARD8 sensing by HIV-1 Gag.
    DOI:  https://doi.org/10.1126/sciadv.adz1069
  2. J Biol Chem. 2025 Nov 07. pii: S0021-9258(25)02772-3. [Epub ahead of print] 110920
    The Hippo Kinases MST1/2 Integrate Sterile and Infectious Signals to Regulate Macrophage Cell Death.
    Sydney M Quagliato, Matthew Gulker, Ryan Mirhosiny, Lucas Meints, Brendyn M St Louis, Yu-Ting Su, Fangyuan Sun, Yuan He, Pei-Chung Lee.
      Mammalian STE20-like kinases MST1 and MST2 are the conserved Hippo kinases known for their importance in organ development and tumor suppression. Notably, humans and mice lacking these kinases have increased susceptibility to infection, indicating a role of MST1/2 in immunity. In macrophages that are critical immune cells in host defense, MST1/2 are proteolytically cleaved to coordinate different forms of programmed cell death, including apoptosis and pyroptosis. This cleavage event occurs when the innate immune sensors, inflammasomes, are activated by the bacterial pathogen, Legionella pneumophila, or damage-associated molecular patterns. In this report, we examine MST1/2 cleavage in macrophages under various inflammatory conditions and challenges with pathogenic bacteria. ATP and nigericin induce MST1/2 cleavage and apoptosis, while the NLRP3 inflammasome and GSDMD-mediated pyroptosis are activated. Remarkably, in conditions that do not support activation of NLRP3 or GSDMD, MST1/2 are still cleaved by caspases to promote cell death in macrophages treated with these molecules. During infection, wildtype macrophages trigger MST1/2 cleavage and apoptosis against L. pneumophila and Yersinia pseudotuberculosis but preferentially activate GSDMD-mediated pyroptosis against Pseudomonas aeruginosa. Interestingly, GSDMD knockout macrophages opt to cleave MST1/2 and undergo apoptosis in response to P. aeruginosa, suggesting an interplay between GSDMD and MST1/2. Together, macrophages funnel apoptotic death signals through MST1/2 cleavage upon stimulation of the inflammatory molecules and pathogens, illustrating the broad implications of the host Hippo kinases in infections and inflammation.
    Keywords:  bacterial pathogenesis; cysteine protease; host defense; post‐translational modification (PTM); proteolysis
    DOI:  https://doi.org/10.1016/j.jbc.2025.110920
  3. Nature. 2025 Nov 12.
    SIGLEC12 mediates plasma membrane rupture during necroptotic cell death.
    Hyunjin Noh, Zeena Hashem, Elena Boms, Ayaz Najafov.
      Necroptosis is a form of lytic cell death that is overactivated during infections and in inflammatory pathologies1. NINJ1 was recently found to be a mediator of plasma membrane rupture (PMR) during pyroptosis, toxin-induced necrosis, apoptosis, and ferroptosis2,3, but the mediator of PMR during necroptotic cell death remained unknown. Here, using a CRISPR-Cas9-based genome-wide knockout approach, we identify SIGLEC12 as a key mediator of necroptosis downstream of MLKL at the PMR step. Cells with knockdown or knockout of SIGLEC12 are defective in necroptosis-induced PMR and demonstrate ballooning morphology. During necroptosis, SIGLEC12 undergoes dephosphorylation, interacts with MLKL, forms cytosolic puncta and assembles into fibrils. Notably, SIGLEC12 is cleaved by TMPRSS4 during necroptosis to produce a 20-kDa fragment highly homologous to NINJ1, and this cleavage event is required and sufficient to induce PMR during necroptosis. A SIGLEC12 variant associated with cancer (Ser458Phe) and a variant found in the general human population (Arg528Trp) attenuate SIGLEC12 cleavage by TMPRSS4. Knockout of Siglec12 in mouse cells does not affect PMR, suggesting a species-specific role. Our identification of SIGLEC12 as a mediator of PMR expands our understanding of how programmed necrosis is executed and offers new approaches for targeting this proinflammatory form of cell death in human diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09741-1
  4. Nat Immunol. 2025 Nov 11.
    Single-cell analysis reveals cell death as driver of NLRP3-mediated secretion of IL-1β in human monocytes.
    Lieselotte Vande Walle, Kentaro Kato, Mai Yamagishi, Takashi Kamatani, Alex Vervaeke, Rosa Martín-Pérez, Masaki Shimizu, Takumi Takizawa, Junko Takita, Ryuta Nishikomori, Osamu Ohara, Kazushi Izawa, Yoshitaka Shirasaki, Mohamed Lamkanfi.
      Interleukin-1β (IL-1β) is a key proinflammatory cytokine with critical roles in infections and inflammatory diseases, yet the mechanisms regulating its release from human monocytes remain unclear. Here we used a suite of single-cell approaches, including integrated live-cell imaging of secretion and cell fate, flow cytometry and high-content imaging, to investigate IL-1β secretion dynamics in lipopolysaccharide-stimulated primary human peripheral blood CD14+ monocytes. We found marked heterogeneity: a large fraction of cells remained viable and contributed negligibly to IL-1β secretion, challenging established models. Instead, a small subset (5-10%) undergoing canonical NLRP3 inflammasome activation and GSDMD-dependent pyroptosis produced the majority of secreted IL-1β, with a smaller contribution from apoptotic cells transitioning to secondary necrosis. Single-cell profiling of CD14+ monocytes from patients with cryopyrin-associated periodic syndrome confirmed lytic cell death as the driver of pathological IL-1β release. These findings redefine IL-1β as a damage-associated molecular pattern, secreted predominantly by dying monocytes.
    DOI:  https://doi.org/10.1038/s41590-025-02319-z
  5. Front Immunol. 2025 ;16 1631152
    Impaired NLRP3 inflammasome signaling diverts pyroptotic to apoptotic caspase activation in macrophages.
    Ying-Qing Gan, Yuan-Wen Cai, Xiu-Wen Liang, Ling-Zhi Wang, Fu-Li Shi, Nuo Sun, Ya-Ping Li, Rong Xu, Bo Hu, Qing-Bing Zha, Xian-Hui He, Tak-Sui Wong, Jin-Hua Li, Dong-Yun Ouyang.
      NLRP3 (NLR family pyrin domain-containing 3) inflammasome is a first line of defense of innate immunity, mediating caspase-1-dependent pyroptosis and cytokine release upon danger signaling. Intervention of NLRP3 innate surveillance may cause defects in this signaling pathway, while the host has evolved alternative ways to combat such intervention. Yet it remains incompletely understood whether NLRP3 sensing of danger signaling can divert pyroptosis to other forms of cell death in circumstances of impaired NLRP3 signaling. In this study, we adopted two macrophage models (delayed delivery of triggering signaling and caspase-1 deficiency) to mimic defects in NLRP3 signaling to address this issue. We found that the NLRP3/ASC platform preferentially recruited caspase-1 rather than caspase-8 in lipopolysaccharide (LPS)-primed macrophages timely triggered with nigericin. However, when the triggering signal (nigericin) was delayed, the recruitment diverted to caspase-8, leading to apoptotic caspase activation. Furthermore, in caspase-1-deficient macrophages, nigericin triggering diverted NLRP3-ASC-caspase-1-driven pyroptosis to caspase-8/-9/-3 activation and GSDME-mediated secondary necrosis. Unexpectedly, VX-765 (a caspase-1 inhibitor) exhibited a pan-caspase inhibitor-like effect, suppressing caspase-8/-9/-3 activation and GSDME cleavage in a dose-dependent manner. Mitochondrial damage was observed in both WT and caspase-1-deficient cells upon nigericin stimulation, suggesting mitochondrial injury being an upstream event in this process. Collectively, our data indicate that NLRP3 inflammasome is poised to divert pyroptotic to apoptotic caspase activation for combating danger signaling when conventional pathway is impaired, highlighting a complex interaction between various forms of cell death pathways.
    Keywords:  LPS tolerance; NLRP3 inflammasome; apoptosis; apoptosome; caspase-8; pyroptosis
    DOI:  https://doi.org/10.3389/fimmu.2025.1631152
  6. Nat Commun. 2025 Nov 13. 16(1): 9822
    Non-apoptotic caspase-8 is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection.
    Stefanie M Bader, Lena Scherer, Reet Bhandari, Allan J Motyer, James P Cooney, Liana Mackiewicz, Merle Dayton, Dylan Sheerin, David V L Romero, Jan Schaefer, Jiyi Pang, Siqi Chen, Kael Schoffer, Le Wang, Xinyi Jin, Daniel Batey, Raymond K H Yip, Ishrat Zaman, Pradeep Rajasekhar, Matthew J Gartner, Stephen Wilcox, Lachlan Whitehead, Smitha Rose Georgy, Ana Maluenda, Kathryn C Davidson, Cody C Allison, Rory Bowden, Kerstin Brinkmann, Marie-Liesse Asselin-Labat, Belinda Phipson, Maria C Tanzer, Marco J Herold, Andre L Samson, James E Vince, Andreas Strasser, Marc Pellegrini, Marcel Doerflinger.
      Inflammation and excess cytokine release are hallmarks of severe COVID-19. While programmed cell death is known to drive inflammation, its role in SARS-CoV-2 pathogenesis remains unclear. Using gene-targeted murine COVID-19 models, we here find that caspase-8 is critical for cytokine release and inflammation. Loss of caspase-8 reduces disease severity and viral load in mice, and this occurs independently of its apoptotic function. Instead, reduction in SARS-CoV-2 pathology is linked to decreased IL-1β levels and inflammation. Loss of pyroptosis and necroptosis mediators in gene-targeted animals provides no additional benefits in mitigating disease outcomes beyond that conferred by loss of caspase-8. Spatial transcriptomic and proteomic analyses of caspase-8-deficient mice confirm that improved outcomes are due to reduced pro-inflammatory responses, rather than changes in cell death signalling. Elevated expression of caspase-8 and cFLIP in infected lungs, alongside caspase-8-mediated cleavage of N4BP1, a suppressor of NF-kB signalling, indicates a role of this signalling axis in pathological inflammation. Collectively, these findings highlight non-apoptotic functions of caspase-8 as a driver of severe COVID-19 through modulation of inflammation, not through the induction of apoptosis.
    DOI:  https://doi.org/10.1038/s41467-025-65098-z
  7. Trends Immunol. 2025 Nov 10. pii: S1471-4906(25)00252-2. [Epub ahead of print]
    Post-translational modifications of NLRP3: to prime or not to prime?
    Océane Dufies, Ivan Zanoni.
      The NLRP3 inflammasome plays a central role in host defense against microbial infections but also contributes to inflammatory diseases. Functioning of NLRP3 strictly relies on two signals: a 'priming signal' that licenses NLRP3 activity and an 'activation signal' that triggers inflammasome assembly and downstream caspase-1 activation. The priming signal involves transcriptional upregulation of NLRP3 and diverse post-translational modifications that regulate its stability, subcellular localization, and protein-protein interactions. This multilayered regulation prevents untimely inflammasome activation while enabling its rapid assembly when both priming and activation signals are present. Here, we focus on the complexity of the priming signal and critically analyze and discuss how diverse post-translational modifications cooperate to prime NLRP3, controlling its activity in health and disease.
    Keywords:  NLRP3; activation; inflammasome; post-translational modifications; priming
    DOI:  https://doi.org/10.1016/j.it.2025.10.008
  8. Nat Commun. 2025 Nov 13. 16(1): 9979
    A glucose kinase-independent HK2 activity prevents TNF-induced cell death by phosphorylating RIPK1.
    Tianhao Zou, Ran Liu, Gengqiao Wang, Guoliang Wang, Zhengting Jiang, Chuanzheng Wang, Weimin Wang, Mao Cai, Shuhua Zhang, Huan Cao, Di Zhang, Xueling Wang, Shenghe Deng, Tongxi Li, Jinyang Gu.
      Tumor necrosis factor (TNF)-induced RIPK1-mediated cell death is implicated in various human diseases. However, the mechanisms RIPK1-mediated cell death is regulated by metabolic processes remain unclear. Here, we identify hexokinase 2 (HK2), a critical regulator of glycolysis, as a suppressor of TNF-induced RIPK1 kinase-dependent cell death through its non-metabolic function. HK2 inhibits RIPK1 kinase activity through constitutively phosphorylation at serine 32 of RIPK1. Inhibition of RIPK1 S32-phosphorylation results in RIPK1 kinase activation and subsequent cell death in response to TNFα stimulation. We further show that HK2 is elevated under pathological conditions including liver ischemia-reperfusion (IR) injury and hepatocellular carcinoma (HCC) via the transcriptional factor HMGA1. Moreover, the upregulation of HK2 in the liver confers protection against liver IR injury mediated by RIPK1 kinase, while depleting HK2 in HCC cells enhances TNFα-induced cell death and synergistically improves the efficacy of anti-PD1 therapy in an HCC model. Thus, the findings reveal a potential therapeutic avenue for RIPK1-related diseases through manipulating HK2 non-metabolic function.
    DOI:  https://doi.org/10.1038/s41467-025-64939-1
  9. Cell Mol Immunol. 2025 Nov 12.
    AIM2 drives inflammatory cell death and monkeypox pathogenesis.
    Jueun Oh, Yun-Ho Hwang, Jihye Lee, Cheong Seok, SuHyeon Oh, Hye Yoon Kim, Nabukenya Mariam, Jaeyoung Ahn, GyeongJu Yu, Jaewoo Park, Hayeon Kim, Suhyun Kim, Seyun Shin, Min-Chul Jung, Jinwoo Gil, Joo Sang Lee, Young Ki Choi, Dokeun Kim, Daesik Kim, You-Jin Kim, SangJoon Lee.
      Monkeypox, a zoonotic disease caused by the monkeypox virus (MPXV), has significant global public health implications. Inflammasomes serve as crucial components of the innate immune system, detecting pathogens and triggering cell death in infected cells to eliminate harmful agents. However, the precise molecular mechanisms governing the activation of inflammasomes during MPXV infection remain largely unclear. Using CRISPR-knockout cytosolic innate immune sensor screening, we identified AIM2 as the sensor for MPXV within the inflammasome, a trigger for inflammatory cell death. Mechanistically, AIM2 forms a complex with essential cell death molecules, including ASC and caspase-1 (CASP1), without interacting with RIPK3 or CASP8. Loss of ASC, CASP1, or gasdermin D (GSDMD) reduced cell death following MPXV infection, whereas loss of GSDME, CASP3, CASP6, CASP7, CASP9, RIPK3, or MLKL did not. Pyroptotic cell death was predominantly observed in infected cells, whereas apoptotic and necroptotic signaling pathways were primarily activated in uninfected bystander cells. Furthermore, we found that the transcription factor IRF1 serves as an upstream regulator of AIM2, controlling AIM2-dependent cell death. In experiments involving AIM2-deficient mice infected with MPXV, we observed a decrease in proinflammatory cytokines, multiple inflammatory cell death pathways, and leukocyte migration, culminating in increased viral spread. CAST/EiJ mice succumbed to high-dose MPXV infection within 8 days, whereas AIM2 inhibition increased survival, with 10% of the mice treated with an AIM2 inhibitor surviving the infection. In a low-dose infection model, AIM2 inhibition reduced IL-1β and IL-18 production, LDH release, and tissue pathology. These findings highlight the critical role of AIM2-mediated inflammasome activation, along with multiple programmed cell death pathways, in shaping the innate immune response to MPXV infection, offering valuable insights for developing therapeutic strategies targeting AIM2 and the broader innate immune response against monkeypox.
    Keywords:  AIM2; Inflammasome; Inflammation; Inflammatory cell death; Innate immunity; Monkeypox virus
    DOI:  https://doi.org/10.1038/s41423-025-01367-7
  10. Sci Adv. 2025 Nov 14. 11(46): eadx7809
    The tumor suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis.
    Sukrut C Kamerkar, Taewook Kang, Radu V Stan, Edward J Usherwood, Henry N Higgs.
      Mitochondria are pivotal regulators of cellular homeostasis, integrating energy metabolism, biosynthesis, and programmed cell death (apoptosis). During apoptosis, mitochondrial outer membrane permeabilization by BCL-2-associated X protein/BCL-2 Homolog Antagonist Killer (BAX/BAK) pores facilitates release of apoptotic factors, while the role of inner mitochondrial membrane (IMM) remodeling remains less understood. Here, we identify serine beta-lactamase-like protein (LACTB), a filament-forming serine protease and tumor suppressor, as a regulator of IMM dynamics during apoptosis. LACTB suppression reduces cytochrome c release and apoptosis, whereas its overexpression promotes these effects. LACTB does not affect BAX or Drp1 recruitment to mitochondria. Rather, LACTB is required for apoptosis-induced mitochondrial remodeling, independent of OPA1 processing. Intriguingly, LACTB knockdown does not affect mitochondrial shape changes induced by CCCP treatment, suggesting that LACTB action is apoptosis-specific. Purified LACTB binds and remodels cardiolipin-enriched membrane nanotubes preferentially over planar lipid membranes, suggesting a direct effect in apoptotic membrane remodeling. Collectively, our findings suggest LACTB to be a mediator of apoptosis-induced IMM remodeling, a possible mechanism for tumor suppression in cancer.
    DOI:  https://doi.org/10.1126/sciadv.adx7809
  11. Cell Host Microbe. 2025 Nov 12. pii: S1931-3128(25)00420-2. [Epub ahead of print]33(11): 1827-1829
    Bacteria block host cell death by protein cut-and-paste.
    Lei Song, Zhao-Qing Luo.
      Bacterial pathogens interfere with host cell signaling by inducing post-translational modifications. In this issue, Xu and colleagues report that the Shigella flexneri effector OspB catalyzes an unusual recombination reaction between pro-death members of the BCL-2 family, creating inactive chimeras that effectively block apoptosis of infected cells, thereby promoting bacterial virulence.
    DOI:  https://doi.org/10.1016/j.chom.2025.10.006
  12. Nat Commun. 2025 Nov 12. 16(1): 9946
    YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis.
    Seungwon Yang, Yan-Hong Cui, Haixia Li, Jiangbo Wei, Gayoung Park, Ming Sun, Michelle Verghese, Emma Wilkinson, Teresa Nam, Linnea Louise Lungstrom, Xiaolong Cui, Tae Young Ryu, Jing Chen, Marc Bissonnette, Chuan He, Yu-Ying He.
      The role of m6A RNA methylation of self non-coding RNA remains poorly understood. Here we show that m6A-methylated self U6 snRNA is recognized by YTHDF2 to reduce its stability and prevent its binding to Toll-like receptor 3 (TLR3), leading to decreased inflammatory responses in human and mouse cells and mouse models. At the molecular level, endosomal U6 snRNA binds to the LRR21 domain in TLR3, independent of m6A methylation, to activate inflammatory gene expression, a mechanism that is distinct from that of the best known synthetic TLR3 agonist poly I:C. Both U6 snRNA and YTHDF2 are localized to endosomes via the transmembrane protein SIDT2, where YTHDF2 functions to prevent the U6-TLR3 interaction. We further show that UVB exposure inhibits YTHDF2 by inducing its dephosphorylation and autophagic protein degradation in human keratinocytes and mouse skin. Skin-specific deletion of Ythdf2 in mice enhanced the UVB-induced skin inflammatory response and promoted tumor initiation. Taken together, our findings demonstrate that YTHDF2 plays a crucial role in controlling inflammation by inhibiting m6A U6-mediated TLR3 activation, suggesting that YTHDF2 and m6A U6 are potential therapeutic targets for preventing and treating inflammation and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-025-64898-7
  13. Nat Commun. 2025 Nov 13. 16(1): 9992
    A Pseudomonas aeruginosa quorum-sensing metabolite manipulates macrophage ferroptosis through a methylation pathway.
    Tianyuan Jia, Fengming Li, Tianzhen Li, Anmin Ren, Peiyi Lu, Yiling Liu, Yachun Zhou, Xiangke Duan, Yang Liu, Lin Zhong, Zhirong Zhang, Chris Soon Heng Tan, Liang Yang.
      Ferroptosis is a type of iron- and lipid peroxidation-dependent programmed cell death that is involved in various diseases. Some pathogens manipulate host ferroptosis for pathogenesis; however, the potential mechanisms of action remain unclear. Pseudomonas aeruginosa is an opportunistic pathogen that relies on iron for its virulence, biofilm formation, and survival. Here, we report that P. aeruginosa employs the quorum-sensing metabolite, Pseudomonas quinolone signal (PQS), to induce ferroptosis in macrophages through a carnosine-N-methyltransferase (CNMT)-transferrin receptor 1 (TFR1) methylation pathway. Specifically, PQS promotes iron-dependent lipid peroxidation to induce ferroptosis in macrophages. Using high-resolution mass spectrometry-based cellular thermal shift assay (MS-CETSA)/thermal proteome profiling, we identify CNMT as the direct intracellular receptor of PQS in macrophages. Mechanistically, PQS binding increases the histidine methyltransferase (His MTase) activity of CNMT, catalysing methylation of TFR1 at His35. This methylation increases TFR1 protein production, resulting in amplified iron acquisition for ferroptosis. Crucially, the PQS-CNMT-TFR1 axis is distinct from canonical bacterial pathogens that exploit host cell death pathways, revealing the unique strategy of P. aeruginosa to exploit host epigenetic machinery.
    DOI:  https://doi.org/10.1038/s41467-025-65142-y
  14. Cell Commun Signal. 2025 Nov 11. 23(1): 487
    Histones present on the surface of late apoptotic cells induce RAGE-mediated phagocytosis.
    Yuqing Li, Xiaoman Zhou, Yan Yang, Congcong Du, Yi-Shi Liu, Zijie Li, Linpei Zhang, Hideki Nakanishi.
      The receptor for advanced glycation end products (RAGE) is a multiligand receptor that can induce phagocytosis in both professional and nonprofessional phagocytes. We found that histones are another ligand for RAGE and that binding between histones and RAGE is increased when DNA is attached to histones. While histones are chromosomal proteins in healthy cells, they are exposed to the cell surface as a complex with DNA in late apoptotic cells. The phagocytosis of late apoptotic cells by either professional or nonprofessional phagocytes is enhanced when histones are present on the surface of dead cells. Thus, histones serve as "eat-me" signals to induce the phagocytosis of dead cells. In RAGE-knockout cells, the phagocytosis of late apoptotic cells was not influenced by the removal of histones, indicating that RAGE is required for the removal of histone-presenting cells. In RAGE-knockout mice, wound healing and removal of dead cells from wound sites are delayed, suggesting that RAGE-mediated phagocytosis functions under physiological conditions.
    Keywords:  Apoptosis phagocytosis; Late apoptotic cells; RAGE histone
    DOI:  https://doi.org/10.1186/s12964-025-02483-7
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