bims-cediti 2025-05-04 papers

bims-cediti

Biomed News

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

Issue of 2025–05–04
twenty-two papers selected by
Kateryna Shkarina, Universität Bonn

Gasdermins in pyroptosis, inflammation, and cancer.
S-acylation in apoptotic and non-apoptotic cell death: a central regulator of membrane dynamics and protein function.
Splicing stress-driven cell death via Z-form nucleic acids.
Modeling Necroptotic and Pyroptotic Signaling in Saccharomyces cerevisiae.
Annexin A: Cell Death, Inflammation, and Translational Medicine.
Activation of the Drosophila innate immune system accelerates growth in cooperation with oncogenic Ras.
Updated insights into the molecular networks for NLRP3 inflammasome activation.
Cnidaria XIAP activates caspase-mediated cell death.
Interferon Gamma Stimulation Fails to Restrict Mycobacterium tuberculosis Growth in Human Monocyte-derived and Alveolar Macrophages.
Activation of the endoplasmic reticulum stress regulator IRE1α compromises pulmonary host defenses.
An atlas of ferroptosis-induced secretomes.
Glutamine limits NLRP3 inflammasome activation and pyroptosis in macrophages by sustaining the IRG1/itaconate axis.
Lactate-induced macrophage HMGB1 lactylation promotes neutrophil extracellular trap formation in sepsis-associated acute kidney injury.
Potential and value of rescuing dying neurons.
Pharmacological inhibition of host pathways enhances macrophage killing of intracellular bacterial pathogens.
Staphylococcus aureus promotes strain-dependent immunopathology during cutaneous leishmaniasis through induction of IL-1β.
Extracellular Traps in Inflammation: Pathways and Therapeutic Targets.
Stepwise neofunctionalization of the NF-κB family member Rel during vertebrate evolution.
Klebsiella pneumoniae ST258 impairs intracellular elastase mobilization and persists within human neutrophils.
ATP-release pannexin channels are gated by lysophospholipids.
Eosinophils and pleural macrophages counter regulate IL-33-elicited airway inflammation via the 12/15-lipoxygenase pathway.
Stress-dependent activation of the Listeria monocytogenes virulence program ensures bacterial resilience during infection.

Trends Mol Med. 2025 Apr 29. pii: S1471-4914(25)00090-5. [Epub ahead of print]

Gasdermins in pyroptosis, inflammation, and cancer.

Rui Min, Yang Bai, Ning-Rui Wang, Xing Liu.

  Pyroptosis is a type of programmed inflammatory cell death characterized by balloon-like swelling, membrane rupture, and the release of inflammatory cytokines and danger signals. Pyroptosis is directly triggered by activated gasdermins (GSDMs) which bind to membrane phospholipids, oligomerize, and form pores in cell membranes. GSDM activation is mediated by various effector proteases via cleavage of the linker region or post-translational modification to release the active N-terminal fragment in response to a variety of pathogenic or intrinsic danger signals. GSDM-mediated pyroptosis is involved in the pathogenesis of an array of infectious and inflammatory diseases and cancers. This review discusses recent advances related to the physiological and pathological functions of GSDM-mediated pyroptosis, as well as therapeutic strategies targeting pyroptosis.

Keywords:  cancer immunology; gasdermins; infection; inflammation; pyroptosis

DOI:  https://doi.org/10.1016/j.molmed.2025.04.003
Biochem Soc Trans. 2025 Apr 29. pii: BST20253012. [Epub ahead of print]53(2):

S-acylation in apoptotic and non-apoptotic cell death: a central regulator of membrane dynamics and protein function.

Rojae Manhertz-Patterson, G Ekin Atilla-Gokcumen.

  Protein lipidation is a collection of important post-translational modifications that modulate protein localization and stability. Protein lipidation affects protein function by facilitating interactions with cellular membranes, changing the local environment of protein interactions. Among these modifications, S-acylation has emerged as a key regulator of various cellular processes, including different forms of cell death. In this mini-review, we highlight the role of S-acylation in apoptosis and its emerging contributions to necroptosis and pyroptosis. While traditionally associated with the incorporation of palmitic acid (palmitoylation), recent findings indicate that other fatty acids can also participate in S-acylation, expanding its functional repertoire. In apoptosis, S-acylation influences the localization and function of key regulators such as Bcl-2-associated X protein and other proteins modulating their role in mitochondrial permeabilization and death receptor signaling. Similarly, in necroptosis, S-acylation of mixed lineage kinase domain-like protein (MLKL) with palmitic acid and very long-chain fatty acids enhances membrane binding and membrane permeabilization, contributing to cell death and inflammatory responses. Recent studies also highlight the role of S-acylation in pyroptosis, where S-acylated gasdermin D facilitates membrane localization and pore assembly upon inflammasome activation. Blocking palmitoylation has shown to suppress pyroptosis and cytokine release, reducing inflammatory activity and tissue damage in septic models. Collectively, these findings underscore S-acylation as a shared and important regulatory mechanism across cell death pathways affecting membrane association of key signaling proteins and membrane dynamics, and offer insights into the spatial and temporal control of protein function.

Keywords:   S-acylation; apoptosis; cell death; necroptosis; palmitoylation; pyroptosis

DOI:  https://doi.org/10.1042/BST20253012
Mol Cell. 2025 May 01. pii: S1097-2765(25)00317-X. [Epub ahead of print]85(9): 1706-1708

Splicing stress-driven cell death via Z-form nucleic acids.

Marat Pavlyukov, Juan Valcárcel.

In this issue of Molecular Cell, He et al.1 and Yang et al.2 unexpectedly find that inhibitors of pre-mRNA splicing induce cell death via formation of RNA-RNA/DNA-RNA hybrids in Z conformation. These Z-nucleic acids are recognized by the protein ZBP1, which activates innate immune signaling.

DOI: https://doi.org/10.1016/j.molcel.2025.04.014
Biomolecules. 2025 Apr 04. pii: 530. [Epub ahead of print]15(4):

Modeling Necroptotic and Pyroptotic Signaling in Saccharomyces cerevisiae.

Óscar Barbero-Úriz, Marta Valenti, María Molina, Teresa Fernández-Acero, Víctor J Cid.

  The yeast Saccharomyces cerevisiae is the paradigm of a eukaryotic model organism. In virtue of a substantial degree of functional conservation, it has been extensively exploited to understand multiple aspects of the genetic, molecular, and cellular biology of human disease. Many aspects of cell signaling in cancer, aging, or metabolic diseases have been tackled in yeast. Here, we review the strategies undertaken throughout the years for the development of humanized yeast models to study regulated cell death (RCD) pathways in general, and specifically, those related to innate immunity and inflammation, with an emphasis on pyroptosis and necroptosis. Such pathways involve the assembly of distinct modular signaling complexes such as the inflammasome and the necrosome. Like other supramolecular organizing centers (SMOCs), such intricate molecular arrangements trigger the activity of enzymes, like caspases or protein kinases, culminating in the activation of lytic pore-forming final effectors, respectively, Gasdermin D (GSDMD) in pyroptosis and MLKL in necroptosis. Even though pathways related to those governing innate immunity and inflammation in mammals are missing in fungi, the heterologous expression of their components in the S. cerevisiae model provides a "cellular test tube" to readily study their properties and interactions, thus constituting a valuable tool for finding novel therapies.

Keywords:  GSDMD; MLKL; Saccharomyces cerevisiae; caspases; humanized yeast; inflammasome; necroptosis; necrosome; pyroptosis; regulated cell death

DOI:  https://doi.org/10.3390/biom15040530
J Inflamm Res. 2025 ;18 5655-5672

Annexin A: Cell Death, Inflammation, and Translational Medicine.

Zibing Qian, Ziyi Li, Xuebin Peng, Yongwu Mao, Xiaorong Mao, Junfeng Li.

  The annexin superfamily proteins, a family of calcium-dependent phospholipid-binding proteins, are involved in a variety of Ca²+-regulated membrane events. Annexin A, expressed in vertebrates, has been implicated in a variety of regulated cell death (RCD) pathways, including apoptosis, autophagy, pyroptosis, ferroptosis, and neutrophil extracellular trap-induced cell death (NETosis). Given that inflammation is a key driver of cell death, the roles of Annexin A in inflammation have been extensively studied. In this review, we discuss the regulatory roles of Annexin A in RCD and inflammation, the development of related targeted therapies in translational medicine, and the application of animal models to study these processes. We also analyze current challenges and discuss future directions for improved diagnostic and therapeutic strategies.

Keywords:  Annexin A; inflammation; regulated cell death; translational medicine

DOI:  https://doi.org/10.2147/JIR.S511439
PLoS Biol. 2025 Apr;23(4): e3003068

Activation of the Drosophila innate immune system accelerates growth in cooperation with oncogenic Ras.

Fabienne Brutscher, Federico Germani, George Hausmann, Lena Jutz, Konrad Basler.

Innate immunity in Drosophila acts as an organismal surveillance system for external stimuli or cellular fitness and triggers context-specific responses to fight infections and maintain tissue homeostasis. However, uncontrolled activation of innate immune pathways can be detrimental. In mammals, innate immune signaling is often overactivated in malignant cells and contributes to tumor progression. Drosophila tumor models have been instrumental in the discovery of interactions between pathways that promote tumorigenesis, but little is known about whether and how the Toll innate immune pathway interacts with oncogenes. Here we use a Drosophila epithelial in vivo model to investigate the interplay between Toll signaling and oncogenic Ras. In the absence of oncogenic Ras (RasV12), Toll signaling suppresses differentiation and induces apoptosis. In contrast, in the context of RasV12, cells are protected from cell death and Dorsal promotes cell survival and proliferation to drive hyperplasia. Taken together, we show that the tissue-protective functions of innate immune activity can be hijacked by pre-malignant cells to induce tumorous overgrowth.

DOI: https://doi.org/10.1371/journal.pbio.3003068
Cell Mol Immunol. 2025 Apr 30.

Updated insights into the molecular networks for NLRP3 inflammasome activation.

Seungwha Paik, Jin Kyung Kim, Hyo Jung Shin, Eun-Jin Park, In Soo Kim, Eun-Kyeong Jo.

  Over the past decade, significant advances have been made in our understanding of how NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes are activated. These findings provide detailed insights into the transcriptional and posttranslational regulatory processes, the structural-functional relationship of the activation processes, and the spatiotemporal dynamics of NLRP3 activation. Notably, the multifaceted mechanisms underlying the licensing of NLRP3 inflammasome activation constitute a focal point of intense research. Extensive research has revealed the interactions of NLRP3 and its inflammasome components with partner molecules in terms of positive and negative regulation. In this Review, we provide the current understanding of the complex molecular networks that play pivotal roles in regulating NLRP3 inflammasome priming, licensing and assembly. In addition, we highlight the intricate and interconnected mechanisms involved in the activation of the NLRP3 inflammasome and the associated regulatory pathways. Furthermore, we discuss recent advances in the development of therapeutic strategies targeting the NLRP3 inflammasome to identify potential therapeutics for NLRP3-associated inflammatory diseases. As research continues to uncover the intricacies of the molecular networks governing NLRP3 activation, novel approaches for therapeutic interventions against NLRP3-related pathologies are emerging.

Keywords:  Inflammatory disease; Licensing; NLRP3 inflammasome; Post-translational modification (PTM); Pyroptosis; Spatiotemporal

DOI:  https://doi.org/10.1038/s41423-025-01284-9
Int J Biol Macromol. 2025 Apr 25. pii: S0141-8130(25)03979-0. [Epub ahead of print]310(Pt 4): 143427

Cnidaria XIAP activates caspase-mediated cell death.

Yuan Chen, Meng Wu, Zihao Yuan, Qingyue Wang, Hang Xu, Li Sun.

  In vertebrates, X-linked inhibitor of apoptosis (XIAP) is a potent inhibitor of apoptosis. XIAP inhibits apoptosis by interacting with proapoptotic caspases via its baculovirus IAP repeat (BIR) domains and mediating caspase ubiquitination via its really interesting new gene (RING) domain and ubiquitin-associated (UBA) domain. In invertebrates, and mainly in arthropods, XIAP is also known as an apoptosis inhibitor. However, no studies on basal metazoan XIAP have been documented to date. In the present work, we examined the biological activity of XIAP from the jellyfish Aurelia coerulea (AcXIAP) and other non-bilaterians. AcXIAP has three BIRs and one RING domain but lacks a UBA domain. AcXIAP enhanced the apoptosis-inducing activity of all four A. coerulea caspases identified in this study, including both initiator and effector clades. AcXIAP activated caspase via one of the BIRs, which bound and stabilized the caspase, and the RING domain, which mediated ubiquitination of the caspase p20 subunit in a lysine-independent manner. Similar caspase-activating properties were also observed in the XIAP of hydra, coral, and sponge. In hydra, XIAP knockdown markedly decreased cell death induced by an apoptosis inducer. Together these results revealed the unconventional function and working mechanism of XIAP in Cnidaria, and shed new light on the functional and structural evolution of XIAP.

Keywords:  Apoptosis; Caspase; Cnidaria; Jellyfish; XIAP

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143427
J Infect Dis. 2025 Apr 26. pii: jiaf220. [Epub ahead of print]

Interferon Gamma Stimulation Fails to Restrict Mycobacterium tuberculosis Growth in Human Monocyte-derived and Alveolar Macrophages.

Mark C Fernandez, Glenna J Peterson, Chris Le, Shawn J Skerrett, Thomas R Hawn.

  We examined whether IFNG restricts Mycobacterium tuberculosis (Mtb) growth in human macrophages across a range of conditions and methods. We observed an IFNG-dependent enhancement of bacterial replication in MCSF-differentiated monocyte-derived macrophages (MDMs, 4.84 x 105 CFU IFNG stimulated versus 2.48 x 105 CFU untreated, P < 0.001) with four Mtb strains. Mtb replication was not restricted by IFNG treatment of alveolar macrophages. In agreement with previous studies, IFNG-stimulated murine bone marrow derived macrophages effectively restricted Mtb replication. These data suggest that Mtb resists IFNG-stimulated immunity within human macrophages with implications for distinct host species immune responses.

Keywords:   Mycobacterium tuberculosis ; innate immunity; interferon gamma; macrophage

DOI:  https://doi.org/10.1093/infdis/jiaf220
Cell Rep. 2025 Apr 30. pii: S2211-1247(25)00403-6. [Epub ahead of print]44(5): 115632

Activation of the endoplasmic reticulum stress regulator IRE1α compromises pulmonary host defenses.

Amit Sharma, Linda M Heffernan, Ky Hoang, Samithamby Jeyaseelan, William N Beavers, Basel H Abuaita.

  The endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is associated with lung infections where innate immune cells are drivers for progression and resolution ammatory cytokinesflammation. Yet, the role of IRE1α in pulmonary innate immune host defense during acute respiratory infection remains unexplored. Here, we found that activation of IRE1α in infected lungs compromises immunity against methicillin-resistant Staphylococcus aureus (MRSA)-induced primary and secondary pneumonia. Moreover, activation of IRE1α in MRSA-infected lungs and alveolar macrophages (AMs) leads to exacerbated production of inflammatory mediators followed by cell death. Ablation of myeloid IRE1α or global IRE1α inhibition confers protection against MRSA-induced pneumonia with improved survival, bacterial clearance, cytokine reduction, and lung injury. In addition, loss of myeloid IRE1α protects mice against MRSA-induced secondary to influenza pneumonia by promoting AM survival. Thus, activation of IRE1α is detrimental to pneumonia, and therefore, it shows potential as a target to control excessive unresolved lung inflammation.

Keywords:  CP: Immunology; Eicosanoids; GBPs; PR8; Type II interferons; UPR; USA300

DOI:  https://doi.org/10.1016/j.celrep.2025.115632
Cell Death Differ. 2025 Apr 25.

An atlas of ferroptosis-induced secretomes.

F Isil Yapici, Eric Seidel, Alina Dahlhaus, Josephine Weber, Christina Schmidt, Adriano de Britto Chaves Filho, Ming Yang, Maria Nenchova, Emre Güngör, Jenny Stroh, Ioanna Kotouza, Julia Beck, Ali T Abdallah, Jan-Wilm Lackmann, Christina M Bebber, Ariadne Androulidaki, Peter Kreuzaler, Almut Schulze, Christian Frezza, Silvia von Karstedt.

Cells undergoing regulated necrosis systemically communicate with the immune system via the release of protein and non-protein secretomes. Ferroptosis is a recently described iron-dependent type of regulated necrosis driven by massive lipid peroxidation. While membrane rupture occurs during ferroptosis, a comprehensive appraisal of ferroptotic secretomes and their potential biological activity has been lacking. Here, we apply a multi-omics approach to provide an atlas of ferroptosis-induced secretomes and reveal a novel function in macrophage priming. Proteins with assigned DAMP and innate immune system function, such as MIF, heat shock proteins (HSPs), and chaperones, were released from ferroptotic cells. Non-protein secretomes with assigned inflammatory function contained oxylipins as well as TCA- and methionine-cycle metabolites. Interestingly, incubation of bone marrow-derived macrophages (BMDMs) with ferroptotic supernatants induced transcriptional reprogramming consistent with priming. Indeed, exposure to ferroptotic supernatants enhanced LPS-induced cytokine production. These results define a catalog of ferroptosis-induced secretomes and identify a biological activity in macrophage priming with important implications for the fine-tuning of inflammatory processes.

DOI: https://doi.org/10.1038/s41418-025-01517-4
FEBS J. 2025 Apr 28.

Glutamine limits NLRP3 inflammasome activation and pyroptosis in macrophages by sustaining the IRG1/itaconate axis.

Xiaoli Chen, Yuanfeng Zhu, Lin Xia, Sen Su, Shijun Fan, Yongling Lu, Qian Chen, Yan Wei, Qianying Huang, Xin Liu, Xi Peng.

  Aberrant activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome increases the release of mature pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and enhances pyroptosis; thereby necessitating tight regulation of the NLRP3 inflammasome. Dysfunctional glutamine metabolism contributes to the pathogenesis of multiple inflammatory disorders, and the precise mechanism remains to be elucidated. Here, we provide evidence that glutamine deprivation enhances NLRP3 inflammasome activation in macrophages. Indeed, the absence of exogenous glutamine specifically enhanced NLRP3 inflammasome assembly, thereby accelerating pyroptosis and promoting the maturation of IL-1β and IL-18. Inhibition of glutaminolysis exhibited a similar effect to glutamine deprivation, whereas this effect was reversed by α-ketoglutarate (α-KG), a tricarboxylic acid (TCA)-cycle intermediate that can be replenished by glutamine supply. We further observed reduced generation of endogenous itaconate by glutamine deprivation and verified that both exogenous supplementation of itaconate derivative and increased endogenous itaconate production by overexpressing immune-responsive gene 1 [IRG1; also known as aconitate decarboxylase 1 (ACOD1)] could replace glutamine to inhibit the NLRP3 inflammasome. Mechanistically, glutamine deprivation decreased the source of substrate and inhibited transcription factor EB (TFEB)-dependent transcriptional upregulation of IRG1, thereby impairing the IRG1/itaconate axis that suppresses the NLRP3 inflammasome. Furthermore, glutamine deficiency was detected in a murine sepsis model, whereas extrinsic glutamine supplementation conferred protection against intestinal inflammation and tissue damage in septic mice. Taken together, our findings provide a novel insight into the link between glutamine metabolism and NLRP3 inflammasome activation, highlighting the target of glutamine metabolism, which holds as a potential therapeutic strategy for inflammatory diseases.

Keywords:  IRG1/itaconate axis; NLRP3 inflammasome; glutamine metabolism; itaconate; pyroptosis

DOI:  https://doi.org/10.1111/febs.70119
Cell Biol Toxicol. 2025 Apr 30. 41(1): 78

Lactate-induced macrophage HMGB1 lactylation promotes neutrophil extracellular trap formation in sepsis-associated acute kidney injury.

Siwei Wei, Zijuan Dai, Lei Wu, Zhen Xiang, Xiaoxiao Yang, Liubing Jiang, Zhen Du.

   BACKGROUND: Neutrophils play a key role in sepsis-associated acute kidney injury (SAKI), a common and life-threatening complication of organ failure. High mobility group box 1 (HMGB1) modulates inflammatory responses and the formation of neutrophil extracellular traps (NETs). The present work aimed to explore whether HMGB1 lactylation promotes NET formation and exacerbates SAKI.
METHODS: Venous blood samples were collected from healthy volunteers and SAKI patients. A SAKI mouse model was established using the cecal ligation and puncture method. A coculture system of macrophage-derived exosomes and neutrophils was established. Macrophage-derived exosomes were isolated and identified. ELISAs, immunofluorescence staining, coimmunoprecipitation, and Western blotting were utilized to determine protein levels.
RESULTS: Elevated blood lactate levels were associated with increased HMGB1 levels in patients with SAKI. In mouse models, lactate increased HMGB1 expression, promoted NET formation, and exacerbated SAKI. Lactate stimulated M1 macrophages to secrete exosomes, leading to the accumulation and release of HMGB1 in the cytoplasm. Additionally, lactate promoted HMGB1 lactylation in macrophages, triggering the release of mitochondrial DNA from neutrophils and activating the cyclic GMP‒AMP synthase/stimulator of interferon genes pathway.
CONCLUSION: This study revealed that lactate-induced HMGB1 lactylation in macrophages plays a role in promoting NET formation in SAKI through the cGAS/STING pathway. These findings suggest that HMGB1 could be a potential target for therapeutic intervention in SAKI.

Keywords:  Acute kidney injury; HMGB1; Lactylation; Macrophages; Neutrophil Extracellular Trap; Sepsis

DOI:  https://doi.org/10.1007/s10565-025-10026-6
Neural Regen Res. 2025 Apr 29.

Potential and value of rescuing dying neurons.

Wenting You, Tos T J M Berendschot, Birke J Benedikter, Carroll A B Webers, Chris P M Reutelingsperger, Theo G M F Gorgels.

   ABSTRACT: Unwarranted death of neurons is a major cause of neurodegenerative diseases. Since mature neurons are postmitotic and do not replicate, their death usually constitutes an irreversible step in pathology. A logical strategy to prevent neurodegeneration would then be to save all neurons that are still alive, i.e. protecting the ones that are still healthy as well as trying to rescue the ones that are damaged and in the process of dying. Regarding the latter, recent experiments have indicated that the possibility of reversing the cell death process and rescuing dying cells is more significant than previously anticipated. In many situations, the elimination of the cell death trigger alone enables dying cells to spontaneously repair their damage, recover, and survive. In this review, we explore the factors, which determine the fate of neurons engaged in the cell death process. A deeper insight into cell death mechanisms and the intrinsic capacity of cells to recover could pave the way for novel therapeutic approaches to neurodegenerative diseases.

Keywords:  apoptosis; dying neurons; neuronal recovery; neurorescue; reversible cell death process

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01134
bioRxiv. 2025 Apr 07. pii: 2025.04.06.647500. [Epub ahead of print]

Pharmacological inhibition of host pathways enhances macrophage killing of intracellular bacterial pathogens.

Ramesh Rijal, Richard H Gomer.

After ingestion into macrophage phagosomes, some bacterial pathogens such as Mycobacterium tuberculosis ( Mtb ) evade killing by preventing phagosome acidification and fusion of the phagosome with a lysosome. Mtb accumulates extracellular polyphosphate (polyP), and polyP inhibits macrophage phagosome acidification and bacterial killing. In Dictyostelium discoideum , polyP also inhibits bacterial killing, and we identified some proteins in D. discoideum that polyP requires to suppress the killing of ingested bacteria. Here, we find that pharmacological inhibition of human orthologues of the D. discoideum proteins, including P2Y1 receptors, mammalian Target of Rapamycin (mTOR), and inositol hexakisphosphate kinase, enhances the killing of Mtb , Legionella pneumophila , and Listeria monocytogenes by human macrophages. Mtb inhibits phagosome acidification, expression of the proinflammatory marker CD54, and autophagy, and increases expression of the anti-inflammatory marker CD206. In Mtb -infected macrophages, the polyP-degrading enzyme polyphosphatase (ScPPX) and inhibitors reversed these effects, with ScPPX increasing CD54 expression more in female macrophages compared to male macrophages. In addition, Mtb inhibits proteasome activity, and some, but not all, inhibitors reversed these effects. While the existence of a dedicated polyP signaling pathway remains uncertain, our findings suggest that pharmacological inhibition of select host proteins can restore macrophage function and enhances the killing of intracellular pathogens.
Importance: Human macrophages engulf bacteria into phagosomes, which then fuse with lysosomes to kill the bacteria. However, after engulfment, pathogenic bacteria such as Mycobacterium tuberculosis , Legionella pneumophila , and Listeria monocytogenes can block phagosome-lysosome fusion, allowing their survival. Here, we show that pharmacological inhibition of specific macrophage proteins reverses these effects and enhances bacterial killing. These findings suggest that targeting host factors involved in these processes may provide a therapeutic strategy to improve macrophage function against infections such as tuberculosis, Legionnaires' disease, and listeriosis.

DOI: https://doi.org/10.1101/2025.04.06.647500
Cell Rep. 2025 Apr 27. pii: S2211-1247(25)00395-X. [Epub ahead of print]44(5): 115624

Staphylococcus aureus promotes strain-dependent immunopathology during cutaneous leishmaniasis through induction of IL-1β.

Victoria Lovins, Camila Farias Amorim, Nélida Robles, Sofía Murga-Garrido, Jamie Ting-Chun Pan, Tej P Singh, Erin DeNardo, Lucas P Carvalho, Edgar M Carvalho, Phillip Scott, Elizabeth A Grice.

  Cutaneous leishmaniasis is a parasitic infection that causes a spectrum of pathology ranging from single, self-healing lesions to disfiguring chronic wounds. In severe disease, uncontrolled inflammation exacerbates tissue damage and delays healing, though the contributing factors are unclear. We previously observed that delayed healing was associated with Staphylococcus aureus in the lesional microbiota of patients with cutaneous leishmaniasis. To investigate how S. aureus impacts immunopathology during leishmania infection, we established a murine model of S. aureus colonization with clinical isolates followed by Leishmania infection. S. aureus triggered early production of interleukin (IL)-1β during Leishmania infection, which was critical for neutrophil recruitment and cutaneous inflammation. S. aureus isolates differentially induced IL-1β and neutrophil recruitment, and isolates that induced greater neutrophil recruitment were resistant to neutrophil killing and persisted longer. We reveal a mechanism whereby S. aureus mediates immunopathology during cutaneous leishmaniasis, suggesting IL-1β as a promising immunomodulatory target for non-healing infections.

Keywords:  CP: Microbiology; Leishmania; Staphylococcus aureus; cutaneous leishmaniasis; microbiota; skin infection

DOI:  https://doi.org/10.1016/j.celrep.2025.115624
Life (Basel). 2025 Apr 08. pii: 627. [Epub ahead of print]15(4):

Extracellular Traps in Inflammation: Pathways and Therapeutic Targets.

Stelvio Tonello, Nicole Vercellino, Davide D'Onghia, Alessia Fracchia, Giulia Caria, Daniele Sola, Paolo Amedeo Tillio, Pier Paolo Sainaghi, Donato Colangelo.

  New roles for immune cells, overcoming the classical cytotoxic response, have been highlighted by growing evidence. The immune cells, such as neutrophils, monocytes/macrophages, and eosinophils, are versatile cells involved in the release of web-like DNA structures called extracellular traps (ETs) which represent a relevant mechanism by which these cells prevent microbes' dissemination. In this process, many enzymes, such as elastase, myeloperoxidase (MPO), and microbicidal nuclear and granule proteins, which contribute to the clearance of entrapped microorganisms after DNA binding, are involved. However, an overproduction and release of ETs can cause unwanted and dangerous effects in the host, resulting in several pathological manifestations, among which are chronic inflammatory disorders, autoimmune diseases, cancer, and diabetes. In this review, we discuss the release mechanisms and the double-edged sword role of ETs both in physiological and in pathological contexts. In addition, we evaluated some possible strategies to target ETs aimed at either preventing their formation or degrading existing ones.

Keywords:  ETosis; ETs; NETosis; NETs; immunity; inflammation; neutrophils; pharmacological approach; strategies; therapies

DOI:  https://doi.org/10.3390/life15040627
Nat Immunol. 2025 May;26(5): 760-774

Stepwise neofunctionalization of the NF-κB family member Rel during vertebrate evolution.

Allison E Daly, Abraham B Chang, Prabhat K Purbey, Kevin J Williams, Shuxing Li, Benjamin D Redelings, George Yeh, Yongqing Wu, Scott D Pope, Byrappa Venkatesh, Sibon Li, Kaylin Nguyen, Joseph Rodrigues, Kelsey Jorgensen, Ananya Dasgupta, Trevor Siggers, Lin Chen, Stephen T Smale.

Adaptive immunity and the five vertebrate NF-κB family members first emerged in cartilaginous fish, suggesting that NF-κB family divergence helped to facilitate adaptive immunity. One specialized function of the NF-κB Rel protein in macrophages is activation of Il12b, which encodes a key regulator of T cell development. We found that Il12b exhibits much greater Rel dependence than inducible innate immunity genes in macrophages, with the unique function of Rel dimers depending on a heightened intrinsic DNA-binding affinity. Chromatin immunoprecipitation followed by sequencing experiments defined differential DNA-binding preferences of NF-κB family members genome-wide, and X-ray crystallography revealed a key residue that supports the heightened DNA-binding affinity of Rel dimers. Unexpectedly, this residue, the heightened affinity of Rel dimers, and the portion of the Il12b promoter bound by Rel dimers were largely restricted to mammals. Our findings reveal major structural transitions in an NF-κB family member and one of its key target promoters at a late stage of vertebrate evolution that apparently contributed to immunoregulatory rewiring in mammalian species.

DOI: https://doi.org/10.1038/s41590-025-02138-2
Microbiol Res. 2025 Mar;pii: S0944-5013(24)00436-1. [Epub ahead of print]292 128035

Klebsiella pneumoniae ST258 impairs intracellular elastase mobilization and persists within human neutrophils.

Federico Birnberg-Weiss, Joselyn E Castro, Jose R Pittaluga, Luis A Castillo, Daiana Martire-Greco, Federico Fuentes, Fabiana Bigi, Sonia A Gómez, Verónica I Landoni, Gabriela C Fernández.

  Klebsiella pneumoniae (Kp) strains of sequence type (ST) 258 producing K. pneumoniae-carbapenemase (KPC) are a major cause of hospital-associated outbreaks and the main contributors of carbapenemase spreading. Here, we deepen into the mechanisms behind the inhibition of neutrophil bactericidal functions mediated by a clinical isolate of Kp ST258 KPC, Kp from now on. We found that NETs formation induced by different stimuli (PMA, ionomycin, Staphylococcus aureus) was significantly reduced in the presence of Kp. We revealed that Kp affects actin polymerization which correlates with impaired mobilization of elastase from azurophilic granules to the nucleus and reduced elastase mobilization towards phagosomes that contain bacteria. In line with these results, Kp survived within neutrophils for 3 h post-challenge without compromising neutrophil viability. We also found that different Kp clinical isolates inhibited NETs formation and actin polymerization. These results describe a strategy of evasion used by Kp to subvert PMN-mediating both intra and extracellular mechanisms of killing, representing a clear advantage for the survival and spreading of this multidrug-resistant bacteria.

Keywords:  Elastase; Immune evasion; Klebsiella pneumoniae; NETs; Neutrophils

DOI:  https://doi.org/10.1016/j.micres.2024.128035
Elife. 2025 May 01. pii: RP107067. [Epub ahead of print]14

ATP-release pannexin channels are gated by lysophospholipids.

Erik Henze, Russell N Burkhardt, Bennett William Fox, Tyler J Schwertfeger, Eric Gelsleichter, Kevin Michalski, Lydia Kramer, Margret Lenfest, Jordyn M Boesch, Hening Lin, Frank C Schroeder, Toshimitsu Kawate.

  In addition to its role as cellular energy currency, adenosine triphosphate (ATP) serves as an extracellular messenger that mediates diverse cell-to-cell communication. Compelling evidence supports that ATP is released from cells through pannexins, a family of membrane proteins that form heptameric large-pore channels. However, the activation mechanisms that trigger ATP release by pannexins remain poorly understood. Here, we discover lysophospholipids as endogenous pannexin activators, using activity-guided fractionation of mouse tissue extracts combined with untargeted metabolomics and electrophysiology. We show that lysophospholipids directly and reversibly activate pannexins in the absence of other proteins. Secretomics experiments reveal that lysophospholipid-activated pannexin 1 leads to the release of not only ATP but also other signaling metabolites, such as 5'-methylthioadenosine, which is important for immunomodulation. We also demonstrate that lysophospholipids activate endogenous pannexin 1 in human monocytes, leading to the release of IL-1β through inflammasome activation. Our results provide a connection between lipid metabolism and purinergic signaling, both of which play major roles in immune responses.

Keywords:  human; inflammasome; large pore channel; lipid signaling; molecular biophysics; secretomics; structural biology; untargeted metabolomics; xenopus

DOI:  https://doi.org/10.7554/eLife.107067
Front Immunol. 2025 ;16 1565670

Eosinophils and pleural macrophages counter regulate IL-33-elicited airway inflammation via the 12/15-lipoxygenase pathway.

Emi Ito, Reika Hayashizaki, Takuro Hosaka, Tsuyoshi Yamane, Jun Miyata, Yosuke Isobe, Makoto Arita.

   Introduction: Fatty acid metabolism plays a crucial role in regulating airway inflammation through the synthesis of lipid mediators. We have previously demonstrated that a 12/15-lipoxygenase (12/15-LOX or Alox15)-derived mediator attenuates IL-33-induced eosinophilic airway inflammation in mice. However, the cellular sources of these mediators remain unclear.
Methods: To identify the cellular sources, we used several cell type-specific conditional 12/15-LOX-deficient mice.
Results: We found that eosinophils and pleural macrophages were the major 12/15-LOX-expressing cell types responsible for attenuating airway inflammation. Eosinophils were the major population of 12/15-LOX-expressing cells found in inflamed lung tissue. In addition, pleural macrophages were the major population of 12/15-LOX-expressing cells in the thoracic cavity and were found to translocate into inflamed lung tissue in response to airway inflammation.
Discussion: This study suggests that eosinophils and pleural macrophages cooperatively regulate eosinophilic airway inflammation via 12/15-LOX expression. Targeting 12/15-LOX metabolism in these cells may offer new therapeutic strategies for severe asthma.

Keywords:  12/15-lipoxygenase; IL-33; eosinophils; lipidomics; pleural macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1565670
mBio. 2025 Apr 30. e0071925

Stress-dependent activation of the Listeria monocytogenes virulence program ensures bacterial resilience during infection.

Mariya Lobanovska, Ying Feng, Jonathan Zhang, Allison H Williams, Daniel A Portnoy.

  Listeria monocytogenes (Lm) is a Gram-positive, facultative intracellular pathogen that uses both a housekeeping (P1) and stress-activated (Sigma B-dependent) promoter (P2) to express the master virulence regulator PrfA. The Sigma B regulon contains over 300 genes known to respond to different stressors. However, the role of Sigma B in the regulation of prfA during the infection remains uncertain. To define pathways that lead to Sigma B-dependent prfA activation, we performed a genetic screen in L2 fibroblasts using ΔP1 Lm that only has the Sigma B-dependent promoter directly upstream of prfA. The screen identified transposon insertions in a large bacterial sensory organelle known as the stressosome. The absence of functional stressosome components resulted in heterogeneity within bacterial populations, with some bacteria behaving like wild type, while other members of the population exhibited defects in either vacuolar escape and/or cell-to-cell spread. We show that the heterogeneity of the stressosome mutants cannot be rescued by constitutive activation of PrfA. These data defined the importance of the stressosome in controlling bacterial homogeneity and characterized the function of the stressosome in robust virulence activation during infection. ΔP1 Lm model provides new opportunities to identify host-specific signals necessary for stressosome-dependent signaling during Listeria pathogenesis.IMPORTANCEMicrobial pathogens must adapt to varying levels of stress to survive. This study uncovered a link between stress sensing and activation of the virulence program in a facultative intracellular pathogen, Listeria monocytogenes. We show that host-imposed stress is sensed by the signaling machinery known as the stressosome to ensure robust and resilient virulence responses in vivo. Stressosome-dependent activation of the master virulence regulator PrfA was necessary to maintain L. monocytogenes homogeneity within the bacteria population during the transition between early and late stages of intracellular infection. This work also provides a model to further characterize how specific stress stimuli affect bacterial survival within the host, which is critical for our understanding of bacterial pathogenesis.

Keywords:  intracellular bacteria; macrophages; pathogenesis; sigma factors; stress adaptation; virulence regulation

DOI:  https://doi.org/10.1128/mbio.00719-25