bims-cediti 2025-09-14 papers

bims-cediti

Biomed News

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

Issue of 2025–09–14
eight papers selected by
Kateryna Shkarina, Universität Bonn

Shigella type-III secretion system effectors counteract the induction of host inflammation and cell death.
Streptococcus pyogenes EVs induce the alternative inflammasome via caspase-4/-5 in human monocytes.
A potent NLRP3 inhibitor effective against both MCC950-sensitive and -resistant inflammation.
Expression of intron-containing HIV-1 RNA induces NLRP1 inflammasome activation in myeloid cells.
TNF signaling maintains local restriction of bacterial founder populations in intestinal and systemic sites during oral Yersinia infection.
CpG-A induces liquid-liquid phase separation of HMGB1 to activate the RAGE-mediated inflammatory pathway.
Damage-induced IL-18 stimulates thymic NK cells limiting endogenous tissue regeneration.
Influenza A virus circumvents the innate immune response through the sequestration of double-stranded RNA.

EMBO J. 2025 Sep 10.

Shigella type-III secretion system effectors counteract the induction of host inflammation and cell death.

Hiroshi Ashida, Tokuju Okano, Tamako Iida, Poramed Onsoi, Chihiro Sasakawa, Toshihiko Suzuki.

  Many enteric bacterial pathogens deliver virulence effectors to counteract host innate immune responses, such as inflammation and cell death, and colonize the intestinal epithelium. However, host cells recognize the disruption of their innate immune signaling by bacterial effectors and induce alternative immune responses, collectively termed "effector-triggered immunity", to clear bacterial pathogens. Here, we describe a mechanism of cell death induction via effector-triggered immunity and the bacterial countermeasures of the pathogen Shigella flexneri. Shigella delivers the OspI effector to inhibit NF-κB activation, which results in caspase-8 activation in return. Deamidation and inactivation of the E2 ubiquitin-conjugating enzyme Ubc13 by OspI results in the inactivation of cIAPs, which serves as a cue to trigger apoptosis and necroptosis. To prevent caspase-8-mediated apoptosis, Shigella delivers OspC1 and inhibits caspase-8 activation via its ADP-riboxanation activity, which however triggers necroptosis. Necroptosis induced as a secondary effector-triggered immunity response by OspC1 is eventually prevented by another Shigella effector, OspD3. The findings of this study reveal a complex multilayered bacterial strategy for circumventing host cell death induction via effector-triggered immunity.

Keywords:   Shigella ; Apoptosis; Caspase-8; Effector; Necroptosis

DOI:  https://doi.org/10.1038/s44318-025-00561-7
EMBO Rep. 2025 Sep 08.

Streptococcus pyogenes EVs induce the alternative inflammasome via caspase-4/-5 in human monocytes.

Kathrin Krause, Sandra Franch Arroyo, Matteo Ugolini, Tonya Kueck, Timothy J Sullivan, Eric J C Gálvez, Matthias Muenzner, Christian Goosmann, Volker Brinkmann, Christian K Frese, Kathirvel Alagesan, Tim Vierbuchen, Holger Heine, Ulrike Resch, Leif E Sander, Emmanuelle Charpentier.

  The sensing of Gram-negative Extracellular Vesicles (EVs) by the innate immune system has been extensively studied in the past decade. In contrast, recognition of Gram-positive EVs by innate immune cells remains poorly understood. Comparative genome-wide transcriptional analysis in human monocytes uncovered that S. pyogenes EVs induce proinflammatory signatures that are markedly distinct from those of their parental cells. Among the 209 genes exclusively upregulated by EVs, caspase-5 prompted us to study inflammasome signaling pathways in depth. We show that lipoteichoic acid (LTA), a structural component of Gram-positive bacterial membranes present on EVs from S. pyogenes and other Gram-positive species, is sensed by TLR2 which triggers the alternative inflammasome composed of NLRP3 and the inflammatory caspases-4/-5 to mount an IL-1β response without inducing cell death. For S. pyogenes, we identify TLR8 as a sensor to mediate caspase-4/-5-dependent IL-1β secretion. Notably, inflammasome activation by intact bacteria is independent of the global virulence regulator CovS in monocytes. Overall, our study highlights a new role for TLR2 and caspase-4/-5 in the recognition of Gram-positive EVs in human monocytes.

Keywords:   Streptococcus pyogenes ; Caspases; Extracellular Vesicles; Inflammasome; Monocytes

DOI:  https://doi.org/10.1038/s44319-025-00558-7
Cell Chem Biol. 2025 Sep 09. pii: S2451-9456(25)00259-4. [Epub ahead of print]

A potent NLRP3 inhibitor effective against both MCC950-sensitive and -resistant inflammation.

Wonyoung Kim, Soyeon Kim, Hawon Woo, Renuka Anil Jojare, Raghvendra Mall, Asia Nicotra, Benedicte F Py, Chinh Ngo, Si Ming Man, Chirag N Patel, Rajendra Karki.

  The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome detects a broad spectrum of pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), initiating inflammatory responses through caspase-1 activation and interleukin (IL)-1β/IL-18 release. Dysregulated NLRP3 activation is implicated in a range of diseases, including infectious diseases, autoinflammatory disorders, metabolic disorders, and cancer, making it an attractive therapeutic target. Here, we identify ZAP-180013 as a potent and selective small-molecule inhibitor of NLRP3 through high-throughput chemical screening. Molecular docking predicted that ZAP-180013 interacts with histidine 698 (H698) in NLRP3; this was validated by H698A substitution, which abolished binding and inhibitory activity. ZAP-180013 effectively inhibited inflammasome activation in human myeloid cells, including those carrying MCC950-resistant NLRP3 mutations. In vivo, systemic administration of ZAP-180013 ameliorated psoriasiform skin inflammation and protected against lipopolysaccharide (LPS)-induced cytokine responses in mice. These findings establish ZAP-180013 as a potent and selective NLRP3 inhibitor with translational potential in both MCC950-sensitive and -resistant inflammatory disease settings.

Keywords:  ASC; GSDMD; HTS; NLRP3 inflammasome; ZAP-180013; caspase-1; cell death; high-throughput screening,; inflammatory cytokines; pyroptosis

DOI:  https://doi.org/10.1016/j.chembiol.2025.08.006
PLoS Biol. 2025 Sep;23(9): e3003320

Expression of intron-containing HIV-1 RNA induces NLRP1 inflammasome activation in myeloid cells.

Sallieu Jalloh, Ivy K Hughes, Hisashi Akiyama, Aldana D Gojanovich, Andres A Quiñones-Molina, Mengwei Yang, Andrew J Henderson, Gustavo Mostoslavsky, Suryaram Gummuluru.

Despite the success of antiretroviral therapy in suppressing plasma viremia in people living with human immunodeficiency virus type-1 (HIV-1), persistent viral RNA expression in tissue reservoirs is observed and can contribute to HIV-1-induced immunopathology and comorbidities. Infection of long-lived innate immune cells, such as tissue-resident macrophages and microglia may contribute to persistent viral RNA production and chronic inflammation. We recently reported that de novo cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) in macrophages and microglia leads to MDA5 and MAVS-dependent innate immune sensing and induction of type I IFN responses, demonstrating that HIV icRNA is a pathogen-associated molecular pattern (PAMP). In this report, we show that cytoplasmic expression of HIV-1 icRNA also induces NLRP1 inflammasome activation and IL-1β secretion in macrophages and microglia in an RLR- and endosomal TLR-independent manner. Infection of both macrophages and microglia with either replication-competent or single-cycle HIV-1 induced IL-1β secretion, which was attenuated when cytoplasmic expression of viral icRNA was prevented. While IL-1β secretion was blocked by treatment with caspase-1 inhibitors or knockdown of NLRP1 or caspase-1 expression in HIV-infected macrophages, overexpression of NLRP1 significantly enhanced IL-1β secretion in an HIV-icRNA-dependent manner. Immunoprecipitation analysis revealed interaction of HIV-1 icRNA, but not multiply-spliced HIV-1 RNA, with NLRP1, suggesting that HIV-1 icRNA sensing by NLRP1 is sufficient to trigger inflammasome activation. Together, these findings reveal a pathway of NLRP1 inflammasome activation induced by de novo expressed HIV icRNA in HIV-infected myeloid cells.

DOI: https://doi.org/10.1371/journal.pbio.3003320
mBio. 2025 Sep 09. e0177925

TNF signaling maintains local restriction of bacterial founder populations in intestinal and systemic sites during oral Yersinia infection.

Stefan T Peterson, Katherine G Dailey, Karthik Hullahalli, Daniel Sorobetea, Rina Matsuda, Jaydeen Sewell, Winslow Yost, Rosemary O'Neill, Suhas Bobba, Nicolai Apenes, Matthew E Sherman, George I Balazs, Charles-Antoine Assenmacher, Arin Cox, Matthew Lanza, Sunny Shin, Matthew K Waldor, Igor E Brodsky.

  Enteroinvasive bacterial pathogens are responsible for an enormous worldwide disease burden that critically affects the young and immunocompromised. Yersinia pseudotuberculosis is a gram-negative enteric pathogen closely related to the plague agent Y. pestis that colonizes intestinal tissues, induces the formation of pyogranulomas along the intestinal tract, and disseminates to systemic organs following oral infection of experimental rodents. Prior studies proposed that systemic tissues were colonized by a pool of intestinal replicating bacteria distinct from populations within Peyer's patches and mesenteric lymph nodes. Whether bacteria within intestinal pyogranulomas serve as the source for systemic dissemination and the relationship between bacterial populations within different tissue sites is poorly defined. Moreover, the host factors that regulate Yersinia colonization and dissemination are not well understood. Here, we demonstrate using sequence tag-based analysis of microbial populations in R (STAMPR) that remarkably small founder populations independently colonize intestinal and systemic tissues. Notably, intestinal pyogranulomas contain clonal populations of bacteria that are restricted and do not spread to other tissues. However, Yersinia populations are shared among systemic organs and the blood, suggesting that systemic dissemination occurs via hematogenous spread. Finally, we demonstrate that TNF signaling is a key contributor to the bottlenecks limiting both initial colonization and subsequent dissemination of orally acquired bacterial populations. Altogether, this study reveals previously undescribed aspects of infection dynamics of enteric bacterial pathogens.IMPORTANCEDissemination of bacteria following intestinal infection can lead to severe disease, including sepsis, organ damage, and death. However, the intestinal bacterial population dynamics governing the colonization of mucosal and systemic tissues and the intestinal sites that seed systemic spread are not clear. Yersinia pseudotuberculosis is a rodent and human intestinal pathogen closely related to the plague agent and provides a natural rodent-adapted model to study systemic bacterial dissemination. Our findings define the infection dynamics of enteric Yersinia and the impact of the innate immune system on Yersinia colonization of the intestine and systemic organs.

Keywords:  Yersinia; bacterial infection; gastrointestinal infection; infection dynamics; infectious disease; innate immunity; tumor necrosis factor

DOI:  https://doi.org/10.1128/mbio.01779-25
Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2505826122

CpG-A induces liquid-liquid phase separation of HMGB1 to activate the RAGE-mediated inflammatory pathway.

Kaihui Peng, Gaohong Fu, Long Chen, Jiazhi Xie, Kai Bao, Jin-Ping Li, Shi-Zhong Luo.

  High-mobility group box protein 1 (HMGB1) is a chromatin-associated nonhistone protein widely distributed in the nucleus of eukaryotic cells. It is transported extracellularly as a proinflammatory mediator or late warning protein to induce immune and inflammatory reactions upon stimuli such as microbial infection. Here, we have found that HMGB1 directly interacts with bacterial DNA analogue CpG-A in the extracellular environment to undergo liquid-liquid phase separation (LLPS) via its positively charged DNA-binding domain. We have demonstrated that the receptor for advanced glycosylation end products (RAGE) responds to stimulation of the extracellular HMGB1-CpG-A complex and triggers phase separation of the downstream adaptor protein, Src76kDa structural domain leukocyte protein (SLP76), which promotes activation of the MAPK pathway and release of inflammatory cytokines. These results not only designate that LLPS serves as a gain-of-function mechanism involved in the axis of DNA-HMGB1 stimulated RAGE-SLP76 signaling pathway but also provide evidence that the activity of HMGB1 is regulated by LLPS, highly relevant to immune responses of inflammatory cells toward microbial infection. Especially, the finding that the intracellular SLP76 forms condensates with the cytosol domain of RAGE may represent a general downstream phenomenon when an inflammatory cell membrane receptor is activated.

Keywords:  HMGB1; RAGE; inflammations; liquid–liquid phase separation; signal transduction

DOI:  https://doi.org/10.1073/pnas.2505826122
Nat Immunol. 2025 Sep 11.

Damage-induced IL-18 stimulates thymic NK cells limiting endogenous tissue regeneration.

David Granadier, Kirsten Cooper, Dante Acenas, Anastasia Kousa, Makya Warren, Vanessa Hernandez, Lorenzo Iovino, Paul deRoos, Emma E Lederer, Steve Shannon-Sevillano, Sinéad Kinsella, Cindy Evandy, Marcel R M van den Brink, Andri Lemarquis, Jarrod A Dudakov.

Interleukin-18 (IL-18) is an acute-phase proinflammatory molecule crucial for mediating viral clearance by activating T helper 1 CD4+ T cells, cytotoxic CD8+ T cells and natural killer (NK) cells. Here, we show that mature IL-18 is generated in the thymus following numerous distinct forms of tissue damage, all of which cause caspase-1-mediated immunogenic cell death. We report that IL-18-stimulated cytotoxic NK cells limit endogenous thymic regeneration, a critical process that ensures the restoration of immune competence after acute insults such as stress, infection, chemotherapy and radiation. NK cells suppress thymus recovery by aberrantly targeting thymic epithelial cells, which act as the master regulators of organ function and regeneration. Together, our data reveal a new pathway regulating tissue regeneration in the thymus and suggest IL-18 as a potential therapeutic target to boost thymic function. Moreover, given the enthusiasm for IL-18 as a cancer immunotherapy due to its capacity to elicit a type 1 immune response, these findings also offer insight into potential off-target effects.

DOI: https://doi.org/10.1038/s41590-025-02270-z
J Virol. 2025 Sep 08. e0073725

Influenza A virus circumvents the innate immune response through the sequestration of double-stranded RNA.

Masahiro Nakano, Sho Miyamoto, Chiho Ohnishi, Chiharu Nogami, Nanami Hirose, Yoko Fujita-Fujiharu, Yukiko Muramoto, Takeshi Noda.

  Double-stranded RNA (dsRNA), which induces an innate immune response against viral infections, is rarely detected in influenza A virus (IAV)-infected cells. Nevertheless, we previously reported that the influenza A viral ribonucleoprotein (vRNP) complex generates looped dsRNAs during RNA synthesis in vitro. This finding suggests that IAV possesses a specific mechanism for sequestering dsRNA within infected cells, thereby enabling viral evasion of the innate immune response. Here, we found that dsRNAs were detected in infected cells lacking the expression of viral non-structural protein 1 (NS1) and nuclear export protein (NEP), both encoded by the same RNA segment. Indeed, the looped dsRNA-vRNP complexes were isolated from IAV-infected cells. Interestingly, NS1 molecules masked the entire looped dsRNA generated by vRNP in vitro, implying a potential role for NS1 in segregating viral dsRNA from cytoplasmic dsRNA sensors. Furthermore, dsRNAs were sequestered within the nucleus of wild-type IAV-infected cells, whereas their translocation to the cytoplasm was observed in NS1-deleted mutant virus-infected cells expressing M1 and NEP. This result indicates the possibility that dsRNA is transported to the cytoplasm in association with vRNP. Notably, the cytoplasmic translocation of dsRNA triggered the nuclear translocation of interferon regulatory factor 3, suggesting the capability of dsRNA in inducing the innate immune response. These findings highlight IAV's distinctive strategy for circumventing innate immunity by sequestration of dsRNAs.IMPORTANCEIt is widely recognized that double-stranded RNA (dsRNA) produced during viral infection triggers an innate immune response. However, the influenza A virus (IAV) has been thought to rarely produce dsRNA within infected cells. Here, we detected dsRNA in the nucleus of IAV-infected cells which lacked the expression of viral non-structural protein 1 (NS1) and nuclear export protein (NEP), both encoded by a single RNA segment. High-speed atomic force microscopy demonstrated that NS1 entirely concealed dsRNA produced by the viral ribonucleoprotein complexes, thereby segregating it from cytoplasmic dsRNA sensors that trigger the innate immune response. Interestingly, cytoplasmic translocation of dsRNA was observed in cells infected with an NS1-deleted mutant virus, where M1 and NEP were expressed, resulting in the nuclear translocation of interferon regulatory factor 3. Collectively, our findings suggest that IAV adeptly sequesters dsRNA to evade the innate immune system.

Keywords:  atomic force microscopy; double-stranded RNA; immunofluorescence assay; influenza virus; innate immune evasion

DOI:  https://doi.org/10.1128/jvi.00737-25