bims-cediti 2025-04-13 papers

bims-cediti

Biomed News

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

Issue of 2025–04–13
eleven papers selected by
Kateryna Shkarina, Universität Bonn

Controlling pyroptosis through post-translational modifications of gasdermin D.
A morphology and secretome map of pyroptosis.
Dysregulation of inflammasomes in autoinflammatory diseases.
The dynamic roles of macrophages extracellular traps (METs) in immune regulation.
A bacterial genotoxin reveals a p53-proteasome-LC3 regulatory axis that drives the suppression of autophagy in cells experiencing sublethal DNA damage.
Teleost GSDMEc regulates GSDMEa-mediated pyroptosis.
Asparagine transporter supports macrophage inflammation via histone phosphorylation.
Mitochondria and cell death signalling.
ATG16L1 restrains macrophage NLRP3 activation and alveolar epithelial cell injury during septic lung injury.
Cyclophilin A and C are the Main Components of Extracellular Vesicles in Response to Hyperglycemia in BV2 Microglial Cells.
When glycobiology meets inflammasome activation: Insights and implications.

Dev Cell. 2025 Apr 07. pii: S1534-5807(25)00067-X. [Epub ahead of print]60(7): 994-1007

Controlling pyroptosis through post-translational modifications of gasdermin D.

Na Zhang, Daichao Xu.

  Pyroptosis, a lytic and programmed cell death pathway, is mediated by gasdermins (GSDMs), with GSDMD playing an important role in innate immunity and pathology. Upon activation, GSDMD is cleaved to release the active N-terminal fragment that oligomerizes into membrane pores, which promote pyroptosis and cytokine secretion, leading to inflammation. Emerging evidence indicates that post-translational modification (PTM) is an important regulatory mechanism of GSDMD activity. This review explores how PTMs, aside from proteolytic cleavage, control GSDMD activity and link biological contexts to pyroptosis in innate immunity and inflammation, which could inform future studies and therapeutic solutions for treating inflammatory conditions.

Keywords:  GSDMD; gasdermin; palmitoylation; phosphorylation; pore forming; post-translational modification; pyroptosis; ubiquitination

DOI:  https://doi.org/10.1016/j.devcel.2025.02.005
Mol Biol Cell. 2025 Apr 09. mbcE25030119

A morphology and secretome map of pyroptosis.

Michael J Lippincott, Jenna Tomkinson, Dave Bunten, Milad Mohammadi, Johanna Kastl, Johannes Knop, Ralf Schwandner, Jiamin Huang, Grant Ongo, Nathaniel Robichaud, Milad Dagher, Andrés Mansilla-Soto, Cynthia Saravia-Estrada, Masafumi Tsuboi, Carla Basualto-Alarcón, Gregory P Way.

Pyroptosis represents one type of Programmed Cell Death (PCD). It is a form of inflammatory cell death that is canonically defined by caspase-1 cleavage and Gasdermin-mediated membrane pore formation. Caspase-1 initiates the inflammatory response (through IL-1β processing), and the N-terminal cleaved fragment of Gasdermin D polymerizes at the cell periphery forming pores to secrete pro-inflammatory markers. Cell morphology also changes in pyroptosis, with nuclear condensation and membrane rupture. However, recent research challenges canon, revealing a more complex secretome and morphological response in pyroptosis, including overlapping molecular characterization with other forms of cell death, such as apoptosis. Here, we take a multimodal, systems biology approach to characterize pyroptosis. We treated human Peripheral Blood Mononuclear Cells (PBMCs) with 36 different combinations of stimuli to induce pyroptosis or apoptosis. We applied both secretome profiling (nELISA) and high-content fluorescence microscopy (Cell Painting). To differentiate apoptotic, pyroptotic and control cells, we used canonical secretome markers and modified our Cell Painting assay to mark the N-terminus of Gasdermin-D. We trained hundreds of machine learning (ML) models to reveal intricate morphology signatures of pyroptosis that implicate changes across many different organelles and predict levels of many pro-inflammatory markers. Overall, our analysis provides a detailed map of pyroptosis which includes overlapping and distinct connections with apoptosis revealed through a mechanistic link between cell morphology and cell secretome.

DOI: https://doi.org/10.1091/mbc.E25-03-0119
Joint Bone Spine. 2025 Apr 05. pii: S1297-319X(25)00062-4. [Epub ahead of print] 105903

Dysregulation of inflammasomes in autoinflammatory diseases.

Cyrielle Hou, Zhuo Wang, Valentin Eichenberger, Fabio Martinon.

Inflammasomes are multiprotein complexes that play a crucial role in the innate immune response by detecting cellular stress and initiating inflammatory signaling through the release of cytokines. When inflammation is dysregulated, it can contribute significantly to the development of autoinflammatory diseases, a group of disorders characterized by inappropriate inflammation in the absence of infection or autoimmunity. This review examines the current understanding of inflammasome dysfunction in various autoinflammatory diseases, highlighting recent advances that connect genetic mutations and environmental triggers to the hyperactivation of inflammasomes. We focus on key inflammasomes, including NLRP1, NLRP3, NLRC4, and Pyrin, and their involvement in disorders such as Cryopyrin-Associated Periodic Syndromes and Familial Mediterranean Fever. Furthermore, we discuss the molecular mechanisms that lead to inflammasome dysregulation, such as gain-of-function mutations. We also review therapeutic approaches targeting these pathways, which show promise in alleviating disease symptoms and improving patient outcomes.

DOI: https://doi.org/10.1016/j.jbspin.2025.105903
Arch Pharm Res. 2025 Apr 05.

The dynamic roles of macrophages extracellular traps (METs) in immune regulation.

Yunjin Shin, Hanyoung Bae, Chaelin Lee, Inmoo Rhee.

  Macrophages are crucial to innate immunity, eliminating pathogens and damaged tissues through phagocytosis and modulating immune responses. Recently, macrophage extracellular traps (METs) have been identified as chromatin-based structures composed of DNA and various immune-related proteins. While METs play a defensive role in trapping and neutralizing pathogens, they are also implicated in disease pathology, contributing to chronic inflammation, tissue damage, and immune dysregulation. The precise mechanisms regulating MET formation are still under investigation, but emerging evidence indicates the involvement of various regulatory factors. Dysregulated MET activity has been associated with various diseases, including autoimmune disorders, cancer, and neurological conditions. A deeper understanding of MET mechanisms and their pathological impact may offer novel therapeutic strategies. Given the limited number of reviews and articles on METs, this review provides valuable insights into MET formation, regulatory pathways, and their role in disease progression.

Keywords:  Autoimmune diseases; Cancer; Inflammation; MET formation; Macrophage extracellular traps (METs); Neutrophil extracellular traps (NETs); Peptidyl arginine deiminase 4 (PAD4)

DOI:  https://doi.org/10.1007/s12272-025-01540-6
iScience. 2025 Apr 18. 28(4): 112118

A bacterial genotoxin reveals a p53-proteasome-LC3 regulatory axis that drives the suppression of autophagy in cells experiencing sublethal DNA damage.

D'Feau J Lieu, Molly K Crowder, Jordan R Kryza, Batcha Tamilselvam, Paul J Kaminski, Ik-Jung Kim, Ying-Xing Li, Eunji Jeong, Michidmaa Enkhbaatar, Henry Chen, Sophia B Son, Hanlin Mok, Kenneth A Bradley, Heidi Phillips, Steven R Blanke.

  Macroautophagy is thought to have a critical role in shaping and refining cellular proteostasis in eukaryotic cells recovering from DNA damage. Autophagy activation has been previously reported in DNA-damaged cells, often in association with increased cellular cytotoxicity. However, we now report a mechanism by which autophagy is suppressed in the absence of cytotoxicity within cells exposed to bacterial toxin-, chemical-, or radiation-mediated sources of genotoxicity. Specifically, our studies demonstrate the DNA damage response-dependent stabilization of the tumor suppressor p53, which is both required and sufficient for regulating the ubiquitination and proteasome-dependent reduction in cellular pools of microtubule-associated protein 1 light chain 3 (LC3A/B), a key precursor of autophagosome biogenesis and maturation, in both epithelial cells and an ex vivo organoid model. Our data indicate that the suppression of autophagy, through a p53-proteasome-LC3 regulatory axis, is a conserved cellular response to multiple sources of genotoxicity. Such a mechanism could provide a means for realigning proteostasis in cells undergoing DNA damage repair.

Keywords:  biological sciences; cell biology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.112118
J Adv Res. 2025 Apr 08. pii: S2090-1232(25)00226-7. [Epub ahead of print]

Teleost GSDMEc regulates GSDMEa-mediated pyroptosis.

Hang Xu, Meng Wu, Yujian Wang, Yaoming Jiao, Yuan Chen, Zihao Yuan, Li Sun.

   INTRODUCTION: Gasdermin (GSDM) is a family of proteins that execute pyroptosis after being activated by caspase (CASP) cleavage. Mammals possess five GSDM members (A - E) with pyroptotic ability. Teleosts possess only one pyroptotic GSDM, GSDME, that exists in three orthologs, GSDMEa, b, and c. GSDMEa and GSDMEb are known to induce pyroptosis, but the function of GSDMEc is unknown.
OBJECTIVES: The present study aimed to elucidate the function of teleost GSDMEc and examine the interplay among teleost GSDME orthologs by using snakehead Channa argus as a representative species.
METHODS: Pyroptosis was assessed via microscopy and biochemical assays. GSDME cleavage, oligomerization, and membrane translocation were examined via immunoblotting. The interactions of GSDME products were examined using confocal microscopy and co-immunoprecipitation. GSDME knockdown in fish and in vivo bacterial infection were performed.
RESULTS: C. argus possessed three GSDME variants (CaGSDMEa, CaGSDMEc1, and CaGSDMEc2). CaGSDMEa was cleaved by C. argus CASP (CaCASP) 1/8 to produce an N-terminal fragment (NT), NT261, that induced pyroptosis. CaGSDMEc1 and CaGSDMEc2 were also cleaved by CaCASP1/8, but the resulting NTs, NT123 and NT108, respectively, were unable to induce pyroptosis. However, both NT123 and NT108 could bind and promote the pyroptotic activity of NT261 by facilitating NT261 oligomerization and membrane translocation. The interaction between NT261 and NT123/NT108 depended on a positively charged motif that is conserved in the metazoan GSDME and is essential to the membrane localization of NT123 and the pyroptotic activity of NT261. Bacterial infection induced CaGSDMEa/CaCASP8 activation and CaGSDMEc1/c2 cleavage in snakehead cells, resulting in pyroptosis, IL-1β/18 maturation cleavage, and extracellular DNA-net formation. CaGSDMEa/c1 knockdown significantly increased bacterial dissemination in fish tissues and reduced fish survival.
CONCLUSIONS: Our results revealed the functions and interactive mechanism of teleost GSDME orthologs, and provided new insights into the regulation of pyroptosis in lower vertebrates.

Keywords:  Caspase; Gasdermin; Pyroptosis; Teleost

DOI:  https://doi.org/10.1016/j.jare.2025.04.007
Sci Adv. 2025 Apr 11. 11(15): eads3506

Asparagine transporter supports macrophage inflammation via histone phosphorylation.

Chuanlong Wang, Yuyi Ye, Muyang Zhao, Qingyi Chen, Bingnan Liu, Wenkai Ren.

Solute carrier (SLC) family is essential for immune responses; nevertheless, whether and how SLCs regulate macrophage inflammation remains unclear. Here, we demonstrate that K636 acetylation mediates high abundance of SLC6A14 in inflammatory macrophages. Notably, the pharmacological inhibition or genetic modulation of SLC6A14 reduces macrophage interleukin-1β (IL-1β) secretion dependently of lower asparagine uptake and subsequently enhanced nuclear LKB1. Mechanistically, nuclear LKB1 lessens MAPK pathway-mediated NLRP3 inflammasome activation by increased histone 3 S10/28 phosphorylation-dependent cyclin O transcription. Moreover, myeloid Slc6a14 deficiency alleviates pulmonary inflammation via suppressing inflammatory macrophage responses. Overall, these results uncover a network by which SLC6A14-mediated asparagine uptake orchestrates macrophage inflammation through histone phosphorylation, providing a crucial target for modulation of inflammatory diseases.

DOI: https://doi.org/10.1126/sciadv.ads3506
Curr Opin Cell Biol. 2025 Apr 10. pii: S0955-0674(25)00048-1. [Epub ahead of print]94 102510

Mitochondria and cell death signalling.

Ella Hall-Younger, Stephen Wg Tait.

Mitochondria are essential organelles in the life and death of a cell. During apoptosis, mitochondrial outer membrane permeabilisation (MOMP) engages caspase activation and cell death. Under nonlethal apoptotic stress, some mitochondria undergo permeabilisation, termed minority MOMP. Nonlethal apoptotic signalling impacts processes including genome stability, senescence and innate immunity. Recent studies have shown that upon MOMP, mitochondria and consequent signalling can trigger inflammation. We discuss how this occurs, and how mitochondrial inflammation might be targeted to increase tumour immunogenicity. Finally, we highlight how mitochondria contribute to other types of cell death including pyroptosis and ferroptosis. Collectively, these studies reveal critical new insights into how mitochondria regulate cell death, highlighting that mitochondrial signals engaged under nonlethal apoptotic stress have wide-ranging biological functions.

DOI: https://doi.org/10.1016/j.ceb.2025.102510
Clin Transl Med. 2025 Apr;15(4): e70289

ATG16L1 restrains macrophage NLRP3 activation and alveolar epithelial cell injury during septic lung injury.

Yan Bai, Xinyu Zhan, Qing Zhu, Xingyue Ji, Yingying Lu, Yiyun Gao, Fei Li, Zhu Guan, Haoming Zhou, Zhuqing Rao.

   BACKGROUND: The lung is the organ most commonly affected by sepsis. Additionally, acute lung injury (ALI) resulting from sepsis is a major cause of death in intensive care units. Macrophages are essential for maintaining normal lung physiological functions and are implicated in various pulmonary diseases. An essential autophagy protein, autophagy-related protein 16-like 1 (ATG16L1), is crucial for the inflammatory activation of macrophages.
METHODS: ATG16L1 expression was measured in lung from mice with sepsis. ALI was induced in myeloid ATG16L1-, NLRP3- and STING-deficient mice by intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Using immunofluorescence and flow cytometry to assess the inflammatory status of LPS-treated bone marrow-derived macrophages (BMDMs). A co-culture system of BMDMs and MLE-12 cells was established in vitro.
RESULTS: Myeloid ATG16L1-deficient mice exhibited exacerbated septic lung injury and a more intense inflammatory response following LPS treatment. Mechanistically, ATG16L1-deficient macrophages exhibited impaired LC3B lipidation, damaged mitochondria and reactive oxygen species (ROS) accumulation. These abnormalities led to the activation of NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), subsequently enhancing proinflammatory response. Overactivated ATG16L1-deficient macrophages aggravated the damage to alveolar epithelial cells and enhanced the release of double-stranded DNA (dsDNA), thereby promoting STING activation and subsequent NLRP3 activation in macrophages, leading to positive feedback activation of macrophage NLRP3 signalling. Scavenging mitochondrial ROS or inhibiting STING activation effectively suppresses NLRP3 activation in macrophages and alleviates ALI. Furthermore, overexpression of myeloid ATG16L1 limits NLRP3 activation and reduces the severity of ALI.
CONCLUSIONS: Our findings reveal a new role for ATG16L1 in regulating macrophage NLRP3 feedback activation during sepsis, suggesting it as a potential therapeutic target for treating sepsis-induced ALI.
KEY POINTS: Myeloid-specific ATG16L1 deficiency exacerbates sepsis-induced lung injury. ATG16L1-deficient macrophages exhibit impaired LC3B lipidation and ROS accumulation, leading to NLRP3 inflammasome activation. Uncontrolled inflammatory responses in ATG16L1-deficient macrophages aggravate alveolar epithelial cell damage. Alveolar epithelial cells release dsDNA, activating the cGAS-STING-NLRP3 signaling pathway, which subsequently triggers a positive feedback activation of NLRP3. Overexpression of ATG16L1 helps mitigate lung tissue inflammation, offering a novel therapeutic direction for sepsis-induced lung injury.

Keywords:  ATG16L; NLRP3 inflammasome; STING; acute lung injury; macrophages

DOI:  https://doi.org/10.1002/ctm2.70289
Mol Neurobiol. 2025 Apr 08.

Cyclophilin A and C are the Main Components of Extracellular Vesicles in Response to Hyperglycemia in BV2 Microglial Cells.

Noelia Castedo, Amparo Alfonso, Rebeca Alvariño, Mercedes R Vieytes, Luis M Botana.

  Cyclophilins (Cyps) and CD147 receptor play a crucial role in the inflammatory responses. Chronic inflammation causes tissue damage and is a common condition of several inflammation-based pathologies as diabetes or Alzheimer´s disease. Under high glucose (HG) conditions, microglia is activated and releases inflammatory mediators. In this process the role of Cyps is unknown, so this study was aimed to investigate the profile of Cyps in microglia and their release through extracellular vesicles (EVs) under hyperglycemia. An increase in reactive oxygen species (ROS) and nitric oxide (NO) levels was observed when BV2 glia cells were incubated with HG concentration. These effects were mitigated by the Cyps inhibitor cyclosporine A (CsA), suggesting the implication of Cyps in BV2 activation. In these conditions the intracellular expression of CypA, B, C and D, as well as the membrane expression of CD147 receptor was increased. In addition, only CypA and CypC were detected in the extracellular medium. Then, the presence of Cyps inside EVs was explored as an alternative secretion route. Interestingly, under HG treatment, an increase in the levels of the four Cyps in EVs was observed. When neurons were treated with EVs derived from HG-treated glia cells, their viability was reduced and EVs were detected in cytosol neurons pointing to an EVs-Cyps neurotoxic effect. These findings provide novel insights into the relationship between Cyps and EVs in neuroinflammation in hyperglycemia conditions. The current results strengthen the role of Cyps in cell communication and its potential role in brain function under pathological conditions.

Keywords:  Cyclophilins; Extracellular vesicles; Hyperglycemia; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1007/s12035-025-04921-6
J Adv Res. 2025 Apr 05. pii: S2090-1232(25)00214-0. [Epub ahead of print]

When glycobiology meets inflammasome activation: Insights and implications.

Hongliang Zhang, Tengchuan Jin, Mengzhou Xue, Songquan Wu, Chunfu Zheng.

   BACKGROUND: Glycobiology focuses mainly on the study of glycan structures and their biological functions. Glycans not only provide a basic energy supply through the tricarboxylic acid cycle and glycolysis but also serve as important immune regulators during pathogen invasion and homeostasis maintenance. Inflammasomes are critical multiprotein complexes of the immune system that detect both exogenous pathogenic threats and endogenous danger signals to mediate inflammatory responses. Glycobiology has revealed significant insights into the mechanisms of immune responses, particularly in the context of inflammasome activation.
AIM OF REVIEW: This review summarizes the multifaceted relationships between glycobiology and inflammasome activation, highlighting how glycan structures, glycosylation patterns, and glycan-binding proteins influence inflammasome pathways. This review sheds light on novel targets for drug development aimed at modulating inflammatory pathways through the targeting of specific glycan structures.
KEY SCIENTIFIC CONCEPTS OF REVIEW: Glycans directly or indirectly provide prime and activation signals for inflammasomes, glycosylation of inflammasome-related proteins by glycan structures modulates inflammasome activation and downstream inflammation, and the interaction between glycans and lectins also provides regulatory signals for inflammasome activation. This intersection of glycobiology and inflammasome activation presents a unique opportunity to elucidate the molecular mechanisms underlying inflammatory responses and their potential therapeutic implications.

Keywords:  Glycans; Glycosylation; Inflammasome; NLRP3; TLRs

DOI:  https://doi.org/10.1016/j.jare.2025.03.054