bims-cediti 2025-04-27 papers

bims-cediti

Biomed News

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

Issue of 2025–04–27
24 papers selected by
Kateryna Shkarina, Universität Bonn

Inflammasomopathies: mechanisms and disease signatures.
Evolutionary and functional analysis of caspase-8 and ASC interactions to drive lytic cell death, PANoptosis.
Multiwalled carbon nanotubes activate the NLRP3 inflammasome-dependent pyroptosis in macrophages.
Discovery of a novel Thiazole amide inhibitor of Inflammasome and Pyroptosis pathways.
The release of NETs during SFTSV infection downregulates the specific inflammatory factors that lead to liver and spleen damage.
Salmonella-NLRP3 Inflammasome Crosstalk: Host Defense Activation Versus Bacterial Immune Evasion Strategies.
Gasdermin D mutation protects against renal ischemia reperfusion injury.
NETs activate AIM2 to mediate synovial fibroblast pyroptosis and promote acute gouty arthritis development.
NLRP11 is required for canonical NLRP3 and non-canonical inflammasome activation during human macrophage infection with mycobacteria.
Genetic Regulation of Cell Death: Insights from Autoinflammatory Diseases.
P62 inhibits IL-1β release during Salmonella Typhimurium infection of macrophages.
Shigella-trained pro-inflammatory macrophages protect zebrafish from secondary infection.
ZBP1 senses splicing aberration through Z-RNA to promote cell death.
Mitochondrial DNA signals driving immune responses: Why, How, Where?
Factor XII-driven coagulation traps bacterial infections.
Unraveling the significance of innate inflammation in vascular disease.
Bidirectional Communication Between the Innate and Adaptive Immune Systems.
Bacterial effector screening reveals RNF214 as a virus restriction factor in mammals.
MyD88-mediated signaling in intestinal fibroblasts regulates macrophage antimicrobial defense and prevents dysbiosis in the gut.
Neutrophil extracellular traps induced by neoadjuvant chemotherapy of breast cancer promotes vascular endothelial damage.
LncRNA JINR1 regulates miR-216b-5p/GRP78 and miR-1-3p/DDX5 axis to promote JEV infection and cell death.
Tau aggregation induces cell death in iPSC-derived neurons.
Macrophage caspase-8 inhibition accelerates necrotic core expansion in atheroma plaque in mice.
Pathogen-induced rerouting of host membrane trafficking.

Trends Immunol. 2025 Apr 21. pii: S1471-4906(25)00082-1. [Epub ahead of print]

Inflammasomopathies: mechanisms and disease signatures.

Sara Cahill, Fiachra Humphries.

  Inflammasomes form in response to infection, cellular stress, or damage. Gain-of-function (GOF) mutations in inflammasome receptors have been identified as the underlying cause of severe inflammatory diseases, termed 'inflammasomopathies'. Recently, molecular interrogation of these diseases revealed several distinctions at the level of the tissue affected, the inflammatory mediators that drive disease progression, and the contribution of programmed cell death. In this review we discuss key emerging differences across inflammasomopathies and the distinct inflammatory patterns seen in patients. We discuss how programmed cell death influences the progression of inflammasomopathies and the role of plasma membrane rupture. Understanding the molecular disease signatures across inflammasomopathies provides crucial insights into identifying and treating the underlying disease and opens new avenues for therapeutic interventions.

Keywords:  NLRC4; NLRP3; gain of function; inflammasomopathies; plasma membrane rupture; pyrin, NLRP1; pyroptosis

DOI:  https://doi.org/10.1016/j.it.2025.03.008
Mol Biol Evol. 2025 Apr 25. pii: msaf096. [Epub ahead of print]

Evolutionary and functional analysis of caspase-8 and ASC interactions to drive lytic cell death, PANoptosis.

Sivakumar Prasanth Kumar, Eswar Kumar Nadendla, R K Subbarao Malireddi, Syed Asfarul Haque, Raghvendra Mall, Andrew F Neuwald, Thirumala-Devi Kanneganti.

  Caspases are evolutionarily conserved proteins essential for driving cell death in development and host defense. Caspase-8, a key member of the caspase family, is implicated in apoptosis, a non-lytic form of cell death, as well as lytic forms of cell death. Recently, caspase-8 has been identified as an integral component of PANoptosomes, multi-protein complexes formed in response to innate immune sensor activation. Several innate immune sensors can nucleate this caspase-8-containing PANoptosome complex to drive inflammatory lytic cell death, PANoptosis. However, how the evolutionarily conserved and diverse functions of caspase-8 drive PANoptosis remains unclear. To address this, we performed evolutionary, sequence, structural, and functional analyses to decode caspase-8's complex-forming abilities and its interaction with the PANoptosome adaptor ASC. Our study distinguished distinct subgroups within the death domain superfamily based on their evolutionary and functional relationships, identified homotypic traits among sub-family members, and captured key events in caspase evolution. We also identified critical residues defining the heterotypic interaction between caspase-8's death effector domain and ASC's pyrin domain, validated through cross-species analyses, dynamic simulations, and in vitro experiments. Overall, our study elucidated recent evolutionary adaptations of caspase-8 that allowed it to interact with ASC, improving our understanding of critical molecular associations in PANoptosome complex formation and the underlying PANoptotic responses in host defense and inflammation. These findings have implications for understanding mammalian immune responses and developing new therapeutic strategies for inflammatory diseases.

Keywords:  ASC; Apoptosis; Arms race; Caspases; Co-evolution; Crosstalk; DED filament; Death domain superfamily; Death fold; Evolution; Helical assembly; Host-pathogen interactions; Inflammasome; Inflammation; Inflammatory response; Innate immunity; Necroptosis; PANoptosis; PANoptosome; PYCARD; Pyroptosis; cell death

DOI:  https://doi.org/10.1093/molbev/msaf096
Mol Pharmacol. 2025 Apr 02. pii: S0026-895X(25)15291-7. [Epub ahead of print]107(5): 100031

Multiwalled carbon nanotubes activate the NLRP3 inflammasome-dependent pyroptosis in macrophages.

Chol Seung Lim, Ja Kook Gu, Qiang Ma.

  Macrophages are major innate immune cells for the clearance of inhaled nanoparticles but may undergo cell death upon phagocytosis of certain nanoparticles due to their resistance to lysosomal degradation and high toxicity to the cell. Here we investigated the pyroptotic effect of exposure to fibrogenic multiwalled carbon nanotubes (MWCNTs) on macrophages, an inflammatory form of cell death. We first evaluated MWCNT-induced cell death in M1 and M2 macrophages that mediate the temporal inflammatory response to MWCNTs in mammalian lungs. Macrophages were differentiated from human monocytic THP-1 cells, followed by polarization to M1 or M2 cells. MWCNTs caused concentration- and time-dependent cytotoxicity in M1 and, to a lesser extent, M2 cells. Carbon black, an amorphous carbonous material control for CNTs, did not cause apparent toxicity in the cells. MWCNTs increased the production and secretion of IL-1β, accompanied by activation of caspase-1, in M1, but not M2, cells. Moreover, MWCNTs induced the formation of apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain specks and the release of cathepsin B in M1 cells, revealing activation of the nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome via lysosomal damage. MWCNTs induced the cleavage of gasdermin D (GSDMD) to form the 31 kDa N-terminal fragment (GSDMD-N), the pore-forming peptide causing pyroptotic cell death. Increased IL-1β release was completely suppressed by AC-YVAD-CMK (a caspase-1 inhibitor), MCC-950 (an NLRP3 inflammasome inhibitor), or CA-074 Me (a cathepsin B inhibitor), alongside the blockage of MWCNT-induced cleavage of GSDMD. The study demonstrates that MWCNTs trigger pyroptosis in M1 macrophages and boost sterile inflammation by activating the NLRP3 inflammasome pathway. SIGNIFICANCE STATEMENT: The nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 inflammasome mediates the inflammatory response to fibrogenic nanoparticles in the lung via multiple means. The current study uncovers the induction of pyroptotic death of macrophages as a major means of nanotoxicity and sterile inflammation via the nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 pathway by nanoparticles.

Keywords:  IL-1β; Inflammation; M1 macrophage; MWCNT; NLRP3; Pyroptosis

DOI:  https://doi.org/10.1016/j.molpha.2025.100031
Bioorg Chem. 2025 Apr 14. pii: S0045-2068(25)00357-8. [Epub ahead of print]160 108477

Discovery of a novel Thiazole amide inhibitor of Inflammasome and Pyroptosis pathways.

Zhen Dai, Ke Wang, Chenli Bai, Yong Li, Quanwei Yu, Zhiping Chen, Jihong Liao, Jianjun Ding, Yuxi Wang.

  Upon the activation of inflammasomes, inflammatory caspases cleave and activate gasdermin D (GSDMD), leading to pore formation that causes cell membrane rupture and amplifies downstream inflammatory responses. Dysregulated inflammasome activation and pyroptosis signaling pathways are implicated in numerous inflammatory diseases. In our work, a set of novel thiazole amide compounds with inhibitory activity against NLRP3 inflammasome-induced pyroptosis was identified. Of all the compounds tested, compound 21 demonstrated the most potent anti-pyroptotic effects. It suppressed GSDMD cleavage and decreased IL-1β and lactate dehydrogenase (LDH) release in a concentration-dependent manner. Compound 21 bound to NLRP3 protein and increased the thermal stability of NLRP3 concentration-dependently. The molecular docking and dynamics simulations revealed that compound 21 binds to the NLRP3 protein's active site, suppressing inflammasome activation. Further investigations showed that compound 21 also partially blocked upstream NF-κB signaling and downstream GSDMD N-terminal domain (GSDMD-NT) oligomerization, which explains its broad inhibitory effects on pyroptosis driven by multiple inflammasomes. Overall, this study presents a promising thiazole amide compound with inhibitory activity against inflammasome activation and subsequent pyroptosis, warranting further exploration.

Keywords:  GSDMD; Inflammasome; Inhibitor; NLRP3; Pyroptosis

DOI:  https://doi.org/10.1016/j.bioorg.2025.108477
J Leukoc Biol. 2025 Apr 25. pii: qiaf053. [Epub ahead of print]

The release of NETs during SFTSV infection downregulates the specific inflammatory factors that lead to liver and spleen damage.

Xuewen Ji, Xinyi Yu, Zihan Xiao, Ruonan Zhang, Zihan Wu, Xinrui Zhang, Chunhui Wang, Jin Zhu, Ye Yang, Tingting Zhou.

  Severe fever with thrombocytopenia syndrome is a life-threatening condition that has been the focus of attention in recent years. It is primarily caused by uncontrolled replication of a novel Bunyavirus and an intense pro-inflammatory response. NETosis is a form of cell death initiated by neutrophils, involving the formation of neutrophil extracellular traps. These NETs are composed of DNA fibers or nuclear chromatin that trap cytoplasmic granule proteins and histones in a meshwork to capture and eliminate pathogens.Our investigation delved into single-cell sequencing data from SFTS patients, revealing that SFTSV can trigger NETosis in both cellular and animal models. Furthermore, we examined the impact of NETs on Thp-1 cells through transcriptome sequencing and evaluated tissues in infected animal models, unveiling a significant down-regulation of specific inflammatory factors. By integrating previous research, we propose a hypothesis that the reduction of these inflammatory factors hinders the occurrence of immune responses and the process of organ repair, thereby causing tissue damage.

Keywords:  Severe fever with thrombocytopenia syndrome virus (SFTSV); inflammatory factors; neutrophil extracellular traps (NETs); tissue damagen; viral infection

DOI:  https://doi.org/10.1093/jleuko/qiaf053
J Inflamm Res. 2025 ;18 5133-5148

Salmonella-NLRP3 Inflammasome Crosstalk: Host Defense Activation Versus Bacterial Immune Evasion Strategies.

Yuxuan Li, Ying Xu, Cheng Jin, Jiayi Qiu, Xinan Jiao, Zhiming Pan, Yaxin Guo.

  The innate immune system plays a crucial role in defending against Salmonella infection. Inflammasomes are macromolecular complexes that assemble in response to the recognition of pathogen- or danger-associated molecular patterns. These complexes serve as signaling platforms for the activation of inflammatory Caspases, which subsequently triggers the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. This process also initiates pyroptosis, a highly inflammatory form of programmed cell death characterized by lytic cell lysis. Salmonella are intracellular pathogens that proliferate within epithelial cells and macrophages, posing a significant public health risk in both developed and developing countries. During Salmonella infection, the canonical NLRP3 and NLRC4 inflammasome, as well as non-canonical inflammasome, are activated. Unlike NLRC4 and non-canonical inflammasomes, which play crucial roles during intestinal infection phases, the role of NLRP3 inflammasome in resisting Salmonella infection demonstrates a higher degree of complexity and uncertainty. Nonetheless, the activation of NLRP3 inflammasome, along with the downstream innate and adaptive responses, form a robust host immune barrier against potential pathogens. Therefore, successful pathogens must evolve multiple mechanisms to circumvent or counteract these immune barriers. Here we review and discuss the mechanisms of NLRP3 inflammasome activation triggered by intracellular Salmonella, as well as the multiple strategies employed by Salmonella to avoid or delay NLRP3 inflammasome activation. A deeper understanding of how NLRP3 inflammasomes recognize Salmonella and how pathogens evade NLRP3 activation has the potential to facilitate the development of novel prevention and control measures for Salmonella infection.

Keywords:  NLRP3; Salmonella; caspases; immune evasion; inflammasome

DOI:  https://doi.org/10.2147/JIR.S519902
Physiol Rep. 2025 Apr;13(8): e70254

Gasdermin D mutation protects against renal ischemia reperfusion injury.

Jennifer S Y Li, Aadhar Moudgil, Daniel N Meijles, Karli Shaw, Sohel M Julovi, Katie Trinh, Stephen I Alexander, Natasha M Rogers.

  Pyroptosis, the most inflammatory form of cell death, is dependent on membrane pore formation governed by the assembly of cleaved Gasdermin D (GSDMD). We hypothesized that regulated necrosis pathways are crucial in the pathophysiology of acute kidney injury (AKI). Mice with an isoleucine-to-asparagine loss-of-function mutation in the Gasdermin D gene (GSDMDI105N/I105N) generated by ethylnitrosourea-mutagenesis were subjected to bilateral renal ischemia-reperfusion injury (IRI) with bio-molecular readouts performed at 24 h. IRI was also performed in mice pretreated with disulfiram. Whole-body irradiation followed by syngeneic bone marrow transplantation generated chimeric mice prior to IRI. Mice homozygous for the GSDMD I105N mutation were protected from IRI, demonstrating lower serum creatinine and reduced histological injury, as well as decreased pro-inflammatory cytokine expression and oxidative stress. Chimeric mice showed that this protection was predominantly governed by mutations in the parenchymal tissue, with a potential contribution from the hematopoietic compartment. Pharmacological inhibition of GSDMD pore formation using disulfiram protected against IRI. Manipulation of GSDMD is an attractive target to mitigate inflammation and cellular death following AKI.

Keywords:  acute kidney injury; gasdermin D; renal tubular epithelial cells

DOI:  https://doi.org/10.14814/phy2.70254
Immunol Lett. 2025 Apr 22. pii: S0165-2478(25)00039-2. [Epub ahead of print]275 107007

NETs activate AIM2 to mediate synovial fibroblast pyroptosis and promote acute gouty arthritis development.

Jing Tian, Ying Liu, Wei Gao, Xiuyun Shi, Feng Cheng, Bing Xie.

   BACKGROUND: Acute gouty arthritis is a metabolic disease characterized by hyperuricemia, with acute attacks involving neutrophil-released NETs activating immune responses through their major component, DNA, as danger-associated molecular patterns (DAMPs).
OBJECTIVE: To investigate whether DNA from NETs activates the AIM2 inflammasome in synovial fibroblasts during acute gouty arthritis attacks, inducing pyroptosis and exacerbating inflammation.
METHODS: The AIM2 gene knockdown mouse model of acute gouty arthritis was constructed, the joint pathological changes were observed by H&E staining, the synovium fibroblasts and neutrophils were sorted by flow cytometry, and the expressions of AIM2, Caspase-1 and GSDMD related proteins were detected by Western blot. The levels of TNF-α, IL-6, IL-1β and IL-18 in serum and cell supernatant were detected by ELISA. Neutrophils were induced to release NETs by urate, and NETs markers (dsDNA, MPO-DNA, NE-DNA) were detected by immunofluorescence (Cit-H3, PAD4) and ELISA. NETs media were co-cultured with synovial fibroblasts, cell activity and migration were evaluated by CCK8 and scrape assay, markers of synovitis (Thy1, VCAM-1, PDPN) were detected by immunofluorescence, and pyroptosis was evaluated by TUNEL and LDH release. By silencing or overexpression of AIM2 gene, Western blot and ELISA, the role of AIM2 in NETs induced pyrodeath and inflammatory response was investigated.
RESULTS: AIM2 gene knockdown significantly alleviated the symptoms of MSU-induced acute gouty arthritis in mice, reducing joint swelling and pathological damage. Expression levels of inflammatory factors (TNF-α, IL-6, IL-1β, IL-18) and cleaved Caspase-1/Caspase-1, GSDMD-NT/GSDMD) were decreased. It was found that neutrophils released NETs in response to sodium urate stimulation, manifested by significant upregulation of Cit-H3 and PAD4, as well as increased dsDNA, MPO-DNA, and NE-DNA complexes. NETs can induce inflammatory response in synovial fibroblasts, which is manifested as decreased cell activity and migration ability, increased release of inflammatory factors, and significantly increased markers of synovitis (Thy1, VCAM-1, PDPN). In addition, NETs induce scorch death of synovium fibroblasts by activating AIM2 inflammatories, which aggravates the inflammatory response, and AIM2 gene knockdown can effectively inhibit the scorch death and inflammatory response induced by NETs, indicating that NETs play a key role in the occurrence and development of gout arthritis through AIM2-mediated scorch death of synovium fibroblasts.
CONCLUSION: NETs-activated AIM2-mediated synovial fibroblast pyroptosis plays a crucial role in acute gouty arthritis, providing a new therapeutic target.

Keywords:  AIM2 inflammasome; Acute gouty arthritis; Nets; Pyroptosis; Synovial fibroblasts

DOI:  https://doi.org/10.1016/j.imlet.2025.107007
mBio. 2025 Apr 24. e0081825

NLRP11 is required for canonical NLRP3 and non-canonical inflammasome activation during human macrophage infection with mycobacteria.

Mateusz Szczerba, Akshaya Ganesh, María Luisa Gil-Marqués, Volker Briken, Marcia B Goldberg.

  The NLRP11 protein is only expressed in primates and participates in the activation of the canonical NLRP3 and non-canonical NLRP3 inflammasome activation after infection with gram-negative bacteria. Here, we generated a series of defined NLRP11 deletion mutants to further analyze the role of NLRP11 in NLRP3 inflammasome activation. Like the complete NLRP11 deletion mutant (NLRP11-/-), the NLRP11 mutant lacking the NAIP, C2TA, HET-E, and TP1 (NACHT) and leucine-rich repeat (LRR) domains (NLRP11∆N_LRR) showed reduced activation of the canonical NLRP3 inflammasome, whereas a pyrin domain mutant (NLRP11∆PYD) had no effect on NLRP3 activation. The NLRP11-/- and NLRP11∆N_LRR mutants, but not the NLRP11∆PYD mutant, also displayed reduced activation of caspase-4 during infection with the intracytosolic, gram-negative pathogen Shigella flexneri. We found that the human-adapted, acid-fast pathogen Mycobacterium tuberculosis and the opportunistic pathogen Mycobacterium kansasii both activate the non-canonical NLRP11 inflammasome in a caspase-4/caspase-5-dependent pathway. In conclusion, we show that NLRP11 functions in the non-canonical caspase-4/caspase-5 inflammasome activation pathway and the canonical NLRP3 inflammasome pathway and that NLRP11 is required for full recognition of mycobacteria by each of these pathways. Our work extends the spectrum of bacterial pathogen recognition by the non-canonical NLRP11-caspase4/caspase-5 pathway beyond gram-negative bacteria.IMPORTANCEThe activation of inflammasome complexes plays a crucial role in intracellular pathogen detection. NLRP11 and caspase-4 are essential for recognizing lipopolysaccharide (LPS), a molecule found in gram-negative bacteria such as the human pathogens Shigella spp., which activate both canonical NLRP3 and non-canonical inflammasome pathways. Through a series of deletion mutants, we demonstrate that the NACHT and LRR domains of NLRP11, but not its pyrin domain, are critical for detection of S. flexneri. Notably, our research reveals that the acid-fast bacterium M. tuberculosis is also detected by NLRP11 and caspase-4, despite not producing LPS. These findings significantly expand the range of pathogens recognized by NLRP11 and caspase-4 to now include acid-fast bacteria that do not contain LPS and underscore the versatility of these innate immune components in pathogen detection.

Keywords:  NLRP11; NLRP3; inflammasomes; innate immunity; macrophages; mycobacteria

DOI:  https://doi.org/10.1128/mbio.00818-25
Annu Rev Immunol. 2025 Apr;43(1): 313-342

Genetic Regulation of Cell Death: Insights from Autoinflammatory Diseases.

Hirotsugu Oda, Alessandro Annibaldi, Daniel L Kastner, Ivona Aksentijevich.

  Metazoans have evolved innate antimicrobial defenses that promote cellular survival and proliferation. Countering the inevitable molecular mechanisms by which microbes sabotage these pathways, multicellular organisms rely on an alternative, perhaps more ancient, strategy that is the immune equivalent of suicide bombing: Infection triggers cell death programs that summon localized or even systemic inflammation. The study of human genetics has now unveiled a level of complexity that refutes the naive view that cell death is merely a blunt instrument or an evolutionary afterthought. To the contrary, findings from patients with rare diseases teach us that cell death-induced inflammation is a sophisticated, tightly choreographed process. We herein review the emerging body of evidence describing a group of illnesses-inborn errors of cell death, which define many of the molecular building blocks and regulatory elements controlling cell death-induced inflammation in humans-and provide a possible road map to countering this process across the spectrum of rare and common illnesses.

Keywords:  IECDs; NF-κB; TNF; apoptosis; autoinflammatory diseases; cell death; inborn errors of cell death; mutations; necroptosis; ubiquitylation

DOI:  https://doi.org/10.1146/annurev-immunol-090222-105848
Front Cell Infect Microbiol. 2025 ;15 1495567

P62 inhibits IL-1β release during Salmonella Typhimurium infection of macrophages.

Nina Judith Hos, Julia Fischer, Ambika M V Murthy, Zahra Hejazi, Martin Krönke, Deniz Hos, Nirmal Robinson.

  Macrophages are critical for the innate immune defense against the facultative intracellular Gram-negative bacterium Salmo\nella enterica serovar Typhimurium. Following phagocytosis by macrophages, S. Typhimurium activates cytoplasmic NLRC3 and NLRP4 inflammasomes, which share the adaptor ASC, resulting in the secretion of the pro-inflammatory cytokine IL-1β. To prevent excessive inflammation and tissue damage, inflammatory signaling pathways are tightly controlled. Recently, autophagy has been suggested to limit inflammation by targeting activated inflammasomes for autophagic degradation. However, the importance of the autophagic adaptor Sequestome-1 (hereafter, p62) for regulating inflammasome activation remains poorly understood. We report here that p62 restricts inflammasome availability and subsequent IL-1β secretion in macrophages infected with S. Typhimurium by targeting the inflammasome adaptor ASC for autophagic degradation. Importantly, loss of p62 resulted in impaired autophagy and increased IL-1β secretion, as well as IL-10 and IFN-β release. In summary, our results demonstrate a novel role for p62 in inducing autophagy and balancing major pro- and anti-inflammatory signaling pathways to prevent excessive inflammation during S. Typhimurium infection of macrophages.

Keywords:  ASC; IFN-I; IFN-β; IL-10; IL-1β; autophagy; inflammasome; p62

DOI:  https://doi.org/10.3389/fcimb.2025.1495567
Cell Rep. 2025 Apr 22. pii: S2211-1247(25)00372-9. [Epub ahead of print]44(5): 115601

Shigella-trained pro-inflammatory macrophages protect zebrafish from secondary infection.

Margarida C Gomes, Dominik Brokatzky, Serge Mostowy.

  Shigella is an important human pathogen that has no licensed vaccine. Despite decades of seminal work suggesting that its pathogenicity relies on inflammatory cell death of macrophages, the in vivo role of macrophages in controlling Shigella infection remains poorly understood. Here, we use a zebrafish model of innate immune training to investigate the antibacterial role of macrophages following a non-lethal Shigella infection. We found that macrophages are crucial for zebrafish larvae survival during secondary Shigella infection. Consistent with signatures of trained immunity, we demonstrate that bacteria are cleared during training and that protection is independent of the secondary infection site. We show that following Shigella training, macrophages have altered mono- and tri-methylation on lysine 4 in histone 3 (H3K4me1/me3) deposition and shift toward a pro-inflammatory state, characterized by increased tumor necrosis factor alpha (TNF-α) expression and antibacterial reactive oxygen species (ROS) production. We conclude that macrophages are epigenetically reprogrammed by Shigella infection to enhance pro-inflammatory and protective responses.

Keywords:  CP: Immunology; CP: Microbiology; Shigella; infection biology; macrophages; trained immunity; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2025.115601
Mol Cell. 2025 Apr 15. pii: S1097-2765(25)00299-0. [Epub ahead of print]

ZBP1 senses splicing aberration through Z-RNA to promote cell death.

Zhang-Hua Yang, Puqi Wu, Bo-Xin Zhang, Cong-Rong Yang, Jia Huang, Lei Wu, Shuang-Hui Guo, Yuenan Zhou, Yuanhui Mao, Yafei Yin, Xiurong Wu, Pu Cheng, Baizhou Li, Rongbin Zhou, Han-Ming Shen, Sheng Nie, Zhi-Yu Cai, Wei Mo.

  RNA splicing, a highly regulated process performed by the spliceosome, is essential for eukaryotic gene expression and cellular function. Numerous cellular stresses, including oncogenic insults, dysregulate RNA splicing, often provoking inflammatory responses and cell death. However, the molecular signals generated by splicing aberrations and the mechanism by which cells sense and respond to these signals remain poorly understood. Here, we demonstrate that spliceosome inhibition induces the widespread formation of left-handed Z-form double-stranded RNA (Z-RNA), predominantly derived from mis-spliced exonic and intronic RNA transcripts in the nucleus. These Z-RNAs are exported to the cytoplasm in a RanGTP-dependent manner. Cytosolic sensing of accumulated Z-RNA by the host sensor Z-DNA-binding protein 1 (ZBP1) initiates cell death, primarily through RIPK3-MLKL-dependent necroptosis. Together, these findings reveal a previously uncharacterized mechanism in which ZBP1-mediated detection of Z-RNA serves as a critical response to global RNA splicing perturbations, ultimately triggering inflammatory cell death.

Keywords:  Z-RNA; ZBP1; necroptosis; spliceosome; splicing aberration

DOI:  https://doi.org/10.1016/j.molcel.2025.03.023
Cell Commun Signal. 2025 Apr 22. 23(1): 192

Mitochondrial DNA signals driving immune responses: Why, How, Where?

Luca Giordano, Sarah A Ware, Claudia J Lagranha, Brett A Kaufman.

  There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.

Keywords:  Circulating cell-free DNA; DNA-sensing receptors; Inflammation; Innate immunity; Mitochondria; Mitochondrial DNA

DOI:  https://doi.org/10.1186/s12964-025-02042-0
J Exp Med. 2025 Jul 07. pii: e20250049. [Epub ahead of print]222(7):

Factor XII-driven coagulation traps bacterial infections.

Katrin F Nickel, Anne Jämsä, Sandra Konrath, Praveen Papareddy, Lynn M Butler, Evi X Stavrou, Maike Frye, Mathias Gelderblom, Bernhard Nieswandt, Sven Hammerschmidt, Heiko Herwald, Thomas Renné.

Blood coagulation is essential for stopping bleeding but also drives thromboembolic disorders. Factor XII (FXII)-triggered coagulation promotes thrombosis while being dispensable for hemostasis, making it a potential anticoagulant target. However, its physiological role remains unclear. Here, we demonstrate that FXII-driven coagulation enhances innate immunity by trapping pathogens and restricting bacterial infection in mice. Streptococcus pneumoniae infection was more severe in FXII-deficient (F12-/-) mice, with increased pulmonary bacterial burden, systemic spread, and mortality. Similarly, Staphylococcus aureus skin infections and systemic dissemination were exacerbated in F12-/- mice. Reconstitution with human FXII restored bacterial containment. Plasma kallikrein amplifies FXII activation, and its deficiency aggravated S. aureus skin infections, similarly to F12-/- mice. FXII deficiency impaired fibrin deposition in abscess walls, leading to leaky capsules and bacterial escape. Bacterial long-chain polyphosphate activated FXII, triggering fibrin formation. Deficiency in FXII substrate factor XI or FXII/factor XI co-deficiency similarly exacerbated S. aureus infection. The data reveal a protective role for FXII-driven coagulation in host defense, urging caution in developing therapeutic strategies targeting this pathway.

DOI: https://doi.org/10.1084/jem.20250049
Int Rev Immunol. 2025 Apr 21. 1-16

Unraveling the significance of innate inflammation in vascular disease.

Alice Valeria Wiyono, Azizah Puspitasari Ardinal, Pradana Pratomo Raharjo.

  Atheroma formation is initiated by the activation of endothelial and smooth muscle cells, as well as immune cells, including neutrophils, lymphocytes, monocytes, macrophages, and dendritic cells. Monocytes, macrophages, and neutrophils are the innate immune cells that provide a rapid initial line of defence against vascular disease. These cells have a short lifespan and cannot retain memories, making them potential therapeutic targets for the inflammatory process associated with atherosclerosis. In addition, macrophages comprise the majority of vessel wall infiltrates and are, therefore, implicated in all stages of atherosclerosis progression. Neutrophils are the most common type of leukocyte found in circulation, and their high levels of matrix-degrading protease explain their significance in fibrous cap destabilization. However, the activation of immune cells becomes more complex by various microenvironmental stimuli and cytokines, which ultimately transform immune cells into their pro-inflammatory state. Different types of macrophage subsets with distinct functions in inflammation, such as M1 macrophages, cause an increase in pro-inflammatory cytokines and produce reactive oxygen species and nitric oxide, further worsening the disease. This review aims to shed light on immune-mediated inflammation in cardiovascular disease by focusing on the role of macrophage subsets in vascular inflammation and plaque stability, as well as the interaction between neutrophils and monocyte-macrophages.

Keywords:  Atherosclerosis; foam cells; innate inflammation; macrophages; plaque stability

DOI:  https://doi.org/10.1080/08830185.2025.2489346
Annu Rev Immunol. 2025 Apr;43(1): 489-514

Bidirectional Communication Between the Innate and Adaptive Immune Systems.

Kathrynne A Warrick, Charles N Vallez, Hannah E Meibers, Chandrashekhar Pasare.

  Effective bidirectional communication between the innate and adaptive immune systems is crucial for tissue homeostasis and protective immunity against infections. The innate immune system is responsible for the early sensing of and initial response to threats, including microbial ligands, toxins, and tissue damage. Pathogen-related information, detected primarily by the innate immune system via dendritic cells, is relayed to adaptive immune cells, leading to the priming and differentiation of naive T cells into effector and memory lineages. Memory T cells that persist long after pathogen clearance are integral for durable protective immunity. In addition to rapidly responding to reinfections, memory T cells also directly instruct the interacting myeloid cells to induce innate inflammation, which resembles microbial inflammation. As such, memory T cells act as newly emerging activators of the innate immune system and function independently of direct microbial recognition. While T cell-mediated activation of the innate immune system likely evolved as a protective mechanism to combat reinfections by virulent pathogens, the detrimental outcomes of this mechanism manifest in the forms of autoimmunity and other T cell-driven pathologies. Here, we review the complexities and layers of regulation at the interface between the innate and adaptive immune systems to highlight the implications of adaptive instruction of innate immunity in health and disease.

Keywords:  CAR-T cells; T cell memory; TNF superfamily; autoimmunity; cytokine storms; microbial defense; sterile inflammation

DOI:  https://doi.org/10.1146/annurev-immunol-083122-040624
PLoS Pathog. 2025 Apr;21(4): e1013035

Bacterial effector screening reveals RNF214 as a virus restriction factor in mammals.

Aaron Embry, David F Schad, Emily A Rex, Neal M Alto, Don B Gammon.

Arboviruses are arthropod-borne viruses that pose significant threats to human and animal health. Previously, we demonstrated that bacterial effector proteins can serve as molecular tools to identify host immunity factors in insect cells that restrict arbovirus replication. In this study, we apply our bacterial effector screening system to identify immunity factors in two mammalian hosts-bats and humans. Our screens identified three bacterial effectors (IpaH4, SopB and SidM) that enhanced the replication of unrelated arboviruses in bat and human cells. We also discovered several effectors that enhanced arbovirus replication in an arbovirus- or host-specific manner. Focusing on the Shigella flexneri-encoded E3 ubiquitin ligase IpaH4, we identified the uncharacterized mammalian really interesting new gene (RING)-domain-containing protein RNF214 as a direct target that is ubiquitinated and degraded by IpaH4. RNF214 belongs to a large family of RING finger (RNF) proteins that primarily function as E3 ubiquitin ligases and that have diverse roles in regulating and mediating innate immune responses to disparate pathogens. Phylogenetic analyses reveal that RNF214 is highly conserved across vertebrate species, suggesting a conserved role in host defense. Functional studies demonstrate that RNF214 overexpression suppresses arbovirus infection in a manner dependent on its putative E3 ubiquitin ligase activity, whereas RNF214 depletion enhances viral replication in both human and bat cells. Furthermore, knockout of RNF214 did not alter the upregulation of interferon (IFN)-stimulated gene expression during infection or upon treatment of cells with IFN. Screening of 11 RNA and DNA viruses, revealed that RNF214 specifically restricts single-stranded RNA (ssRNA) viruses. These findings establish RNF214 as a critical component of the innate immune response against ssRNA viruses that may function independently of the IFN response. More broadly, our work highlights the utility of bacterial effector proteins as powerful tools for uncovering novel antiviral machinery in mammals.

DOI: https://doi.org/10.1371/journal.ppat.1013035
Cell Rep. 2025 Apr 20. pii: S2211-1247(25)00324-9. [Epub ahead of print]44(5): 115553

MyD88-mediated signaling in intestinal fibroblasts regulates macrophage antimicrobial defense and prevents dysbiosis in the gut.

Marina Chulkina, Hanh Tran, Gabriela Uribe, Steven Bruce McAninch, Christina McAninch, Ashley Seideneck, Bing He, Matthew Lanza, Kamil Khanipov, Georgiy Golovko, Don W Powell, Emily R Davenport, Irina V Pinchuk.

  Fibroblasts that reside in the gut mucosa are among the key regulators of innate immune cells, but their role in the regulation of the defense functions of macrophages remains unknown. MyD88 is suggested to shape fibroblast responses in the intestinal microenvironment. We found that mice lacking MyD88 in fibroblasts showed a decrease in the colonic antimicrobial defense, developing dysbiosis and aggravated dextran sulfate sodium (DSS)-induced colitis. These pathological changes were associated with the accumulation of Arginase 1+ macrophages with low antimicrobial defense capability. Mechanistically, the production of interleukin (IL)-6 and CCL2 downstream of MyD88 was critically involved in fibroblast-mediated support of macrophage antimicrobial function, and IL-6/CCL2 neutralization resulted in the generation of macrophages with decreased production of the antimicrobial peptide cathelicidin and impaired bacterial clearance. Collectively, these findings revealed a critical role of fibroblast-intrinsic MyD88 signaling in regulating macrophage antimicrobial defense under colonic homeostasis, and its disruption results in dysbiosis, predisposing the host to the development of intestinal inflammation.

Keywords:  CP: Immunology; MyD88; antimicrobial defense; dysbiosis; fibroblasts; gut; macrophages

DOI:  https://doi.org/10.1016/j.celrep.2025.115553
Breast Cancer Res. 2025 Apr 23. 27(1): 61

Neutrophil extracellular traps induced by neoadjuvant chemotherapy of breast cancer promotes vascular endothelial damage.

Linghui Kong, Song Hu, Ying Zhao, Yan Huang, Xiaobing Xiang, Yang Yu, Xiaochun Mao, Kangjie Xie, Xiaoyan Zhu, Pingbo Xu.

   BACKGROUND: The mechanisms underpinning neoadjuvant chemotherapy-induced vascular endothelial injury in breast cancer remain elusive. Our study aims to demonstrate that Neutrophil Extracellular Traps (NETs) play a pivotal role in neoadjuvant chemotherapy-induced vascular endothelial injury in breast cancer, elucidating that chemotherapy-induced upregulation of Solute Carrier 11a1 (Slc11a1) modulates Reactive Oxygen Species (ROS) generation, which may be critical for NETs formation.
METHODS: We investigated the impact of neoadjuvant chemotherapy for breast cancer on NETs formation and vascular endothelial injury by analyzing NETs dsDNA and serum markers in patients, cells, and chemotherapy mouse models. RNA sequencing of neutrophils from chemotherapy mouse models was performed to identify the potential NETs formation-associated gene Slc11a1, which was further validated through cellular and animal experiments by assessing Slc11a1 expression, intracellular ferrous ion content, and ROS levels. Knockdown of Slc11a1 in human neutrophils and mouse models were also performed to further confirm the phenotypic results.
RESULTS: Our study revealed that plasma NETs formation and endothelial injury markers were significantly elevated in breast cancer patients undergoing docetaxel & carboplatin (TCb) neoadjuvant chemotherapy, compared to controls. In these patients, NETs formation was associated with the augmentation of endothelial injury markers. Chemotherapy mouse models demonstrated that TCb treatment markedly elevated NETs formation and endothelial injury, which can be mitigated by CI-amidine, a protein-arginine deiminase inhibitor. In human neutrophils, we demonstrated that the TCb chemotherapeutic agents (combination of docetaxel and carboplatin) induced the formation of NETs, which subsequently facilitated damage to human umbilical vein endothelial cells in vitro. RNA sequencing of mouse neutrophils identified Slc11a1 as a key NETs formation-related gene, which was upregulated by TCb chemotherapy in neutrophils, leading to increased intracellular ferrous ion content and ROS generation. Knockdown of Slc11a1 in human neutrophils and mouse models demonstrated its reversal effect on TCb-induced ferrous ion upregulation, ROS generation, and NETs formation.
CONCLUSIONS: Our research underscores the capacity of TCb neoadjuvant chemotherapy in breast cancer to augment NETs formation in neutrophils through Slc11a1-mediated ROS generation, which is linked to vascular endothelial injury. Our study elucidates the potential mechanisms underlying perioperative vascular endothelial injury in breast cancer patients undergoing neoadjuvant chemotherapy, offering novel insights into perioperative therapeutic management strategies for these patients.

Keywords:  Neoadjuvant chemotherapy; Neutrophil extracellular traps; Reactive oxygen species; Solute carrier 11a1; Vascular endothelial cells

DOI:  https://doi.org/10.1186/s13058-025-02011-y
J Virol. 2025 Apr 24. e0006625

LncRNA JINR1 regulates miR-216b-5p/GRP78 and miR-1-3p/DDX5 axis to promote JEV infection and cell death.

Shraddha Tripathi, Suryansh Sengar, Anirban Basu, Vivek Sharma.

  Japanese encephalitis virus (JEV) infection in the central nervous system (CNS) leads to neuroinflammation and neuronal cell death. Several long non-coding RNAs (lncRNAs) are differentially expressed during viral infection and regulate multiple aspects of viral pathogenesis. Previously, we have shown that JEV/West Nile virus (WNV) infection promotes JEV-induced non-coding RNA 1 (JINR1) expression in SH-SY5Y cells, and it interacts with RNA-binding motif protein 10 (RBM10) to enhance cell death and viral replication. In this study, we show that JEV or WNV infection of the SH-SY5Y cells inhibits the expression of microRNAs (miRNAs) miR-216b-5p and miR-1-3p. These miRNAs bind to the JEV/WNV genome, and their overexpression during JEV/WNV infection reduces viral replication and cell death. Depleting JINR1 or RBM10 during viral infection prevents the downregulation of miR-216b-5p and miR-1-3p. In addition, JINR1 or RBM10 knockdown during JEV/WNV infection enhances the binding of RNA Pol II and H3K4me3 at the promoters of miR-216b-5p and miR-1-3p. JINR1 or RBM10 depletion also prevents the binding of H3K27me3 at the promoters of these miRNAs, suggesting that JINR1 and RBM10 are involved in their transcription repression. Interestingly, JINR1 also acts as a competing endogenous RNA (ceRNA) that directly binds to miR-216b-5p and miR-1-3p, resulting in the upregulation of their targets glucose-regulated protein 78 (GRP78) and DEAD-Box Helicase 5 (DDX5), respectively, which are involved in regulating viral replication. Our findings suggest that JINR1 uses multiple mechanisms to promote JEV and WNV infection in neuronal cells.
IMPORTANCE: Infection of the central nervous system (CNS) by Japanese encephalitis virus (JEV) or West Nile virus (WNV) leads to neuroinflammation and neuronal cell death. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) regulate viral infection by regulating the expression of host genes. However, knowledge about the interplay between lncRNAs and miRNAs during JEN/WNV infection is limited. We show that JEV/WNV infection inhibits the expression of anti-viral host miRNAs miR-216b-5p and miR-1-3p. These miRNAs inhibit the JEV and WNV replication by directly binding with their genome. JINR1 and its interacting protein, RBM10, inhibit the transcription of miR-216b-5p and miR-1-3p. Interestingly, JINR1 also binds and sequesters miR-216b-5p and miR-1-3p, resulting in upregulation of their targets GRP78 and DDX5, respectively, which promote viral infection. Our findings suggest that lncRNA JINR1 is a potential target for developing anti-virals against JEV/WNV infection.

Keywords:  DDX5; GRP78; JEV; JINR1; LINC01518; RBM10; WNV; miR-1-3p; miR-216b-5p

DOI:  https://doi.org/10.1128/jvi.00066-25
Aging Brain. 2025 ;7 100136

Tau aggregation induces cell death in iPSC-derived neurons.

Hirokazu Tanabe, Sumihiro Maeda, Etsuko Sano, Norio Sakai, Setsu Endoh-Yamagami, Hideyuki Okano.

  Abnormal accumulation of tau proteins in the brain is a hallmark of neurodegenerative diseases such as Alzheimer's disease and is closely linked with neuronal cell death. Tau accumulation is a prominent therapeutic target for Alzheimer's disease, since tau accumulation correlates well with the disease progression, and tau-targeting drugs hold potentials to halt the disease progression. Given the differential response of human and mouse neuronal cells, there is a critical need for a human cellular platform to quickly screen for tau-related neurodegenerative disease therapeutics. However, inducing rapid, tau-dependent neuronal cell death in human models remains challenging. In this study, we established a human cellular model capable of inducing tau aggregation-dependent neuronal cell death within two weeks via tau overexpression. Additionally, we demonstrated the neuroprotective efficacy of known tau-targeting compounds within this system. These findings suggest that our cellular model recapitulates the molecular pathogenesis of tau-induced neurodegeneration and could serve as a valuable platform for drug screening in tauopathies.

Keywords:  Aggregation; Neuronal cell death; Overexpression; Tau; iPSC

DOI:  https://doi.org/10.1016/j.nbas.2025.100136
Front Immunol. 2025 ;16 1513637

Macrophage caspase-8 inhibition accelerates necrotic core expansion in atheroma plaque in mice.

Thomas Pilot, Stéphanie Solier, Antoine Jalil, Charlène Magnani, Tom Vanden Berghe, Peter Vandenabeele, David Masson, Eric Solary, Charles Thomas.

   Background and aims: Cell death plays a central role in atheroma plaque progression and aggravation. This study investigates the role of caspase-8 in regulating macrophage cell death modalities, specifically apoptosis and necroptosis, within atheroma plaques.
Methods: Bone marrow from caspase-8-deficient (Casp8komac ) and cohoused wildtype littermates were transplanted in atherosclerosis-prone Ldlr-/- recipient mice fed with a proatherogenic diet. Aortic plaque development, necrotic core formation, and cell death were analyzed through histological and biochemical assays. In vitro investigation of macrophages exposed to atherogenic stimuli assessed the effects of caspase-8 inhibition on apoptotic and necroptotic pathways.
Results: Despite lower plasma cholesterol levels and reduced number of inflammatory monocytes, caspase-8-deficient mice exhibited more pronounced atherosclerotic lesions with enlarged necrotic cores and an increased number of dead cells. In vitro, in macrophages exposed to oxidized LDL or oxysterols, the inhibition of caspase-8 revealed a shift from apoptosis to necroptosis as confirmed by increased phosphorylation of MLKL along with decreased cleavage of caspase-3 and -7.
Discussion and perspectives: The study highlights the role of caspase-8 in atherosclerosis in tuning the balance between apoptosis and necroptosis. Caspase-8 inhibition leads to a switch towards necroptosis and accumulation of dead cell corpses that contributes to enhanced plaque severity. These findings suggest that reducing caspase-8-regulated necroptosis and necrosis in macrophages could represent a therapeutic strategy to stabilize plaques and reduce cardiovascular risk.

Keywords:  apoptosis; atherosclerosis; caspase-8; macrophages; necroptosis; necrotic core

DOI:  https://doi.org/10.3389/fimmu.2025.1513637
Curr Opin Cell Biol. 2025 Apr 21. pii: S0955-0674(25)00058-4. [Epub ahead of print]94 102520

Pathogen-induced rerouting of host membrane trafficking.

Patrick J Woida, Rebecca L Lamason.

Eukaryotic cell membranes are protective barriers that precisely control cargo import, trafficking, and export. In defiance of this control, intracellular bacterial pathogens forcefully invade host cells and establish intracellular niches. These pathogens require remarkable membrane remodeling events to support their large size, and a significant amount of work has examined how these pathogens co-opt cytoskeleton dynamics to remodel host membranes. Until recently, less attention was given to where the membranes came from to support remodeling around the pathogens at each stage of infection. In this review, we highlight recent examples of how bacterial pathogens reroute membrane trafficking to provide the membranes needed during invasion, intracellular growth, and eventual dissemination through host tissues. The examples discussed underscore emerging themes and areas for continued investigation rather than provide a survey of the entire field. We hope that highlighting these open questions will inspire researchers across disciplines to recognize the importance of pathogens as tools to understand both mechanisms of bacterial virulence and membrane trafficking.

DOI: https://doi.org/10.1016/j.ceb.2025.102520