bims-inflin 2025-03-09 papers

bims-inflin

Biomed News

on Inflammasome and infection

Issue of 2025–03–09
ten papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

TBK1 and IKKε prevent premature cell death by limiting the activity of both RIPK1 and NLRP3 death pathways.
Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection.
Cross-kingdom-mediated detection of intestinal protozoa through NLRP6.
Norovirus co-opts NINJ1 for selective protein secretion.
Caspase-11 and NLRP3 exacerbate systemic Klebsiella infection through reducing mitochondrial ROS production.
LPS binding caspase activation and recruitment domains (CARDs) are bipartite lipid binding modules.
The immunometabolic topography of tuberculosis granulomas governs cellular organization and bacterial control.
Mitochondria sense bacterial lactate and drive release of neutrophil extracellular traps.
Epigenetic regulation of transcription factors involved in NLRP3 inflammasome and NF-kB signaling pathways.
Methionine metabolite spermidine inhibits tumor pyroptosis by enhancing MYO6-mediated endocytosis.

Sci Adv. 2025 Mar 07. 11(10): eadq1047

TBK1 and IKKε prevent premature cell death by limiting the activity of both RIPK1 and NLRP3 death pathways.

Fabian A Fischer, Benjamin Demarco, Felicia Chan Hui Min, Hui Wen Yeap, Dominic De Nardo, Kaiwen W Chen, Jelena S Bezbradica.

The loss of TBK1, or both TBK1 and the related kinase IKKε, results in uncontrolled cell death-driven inflammation. Here, we show that the pathway leading to cell death depends on the nature of the activating signal. Previous models suggest that in steady state, TBK1/IKKε-deficient cells die slowly and spontaneously predominantly by uncontrolled tumor necrosis factor-RIPK1-driven death. However, upon infection of cells that express the NLRP3 inflammasome, (e.g., macrophages), with pathogens that activate this pathway (e.g., Listeria monocytogenes), TBK1/IKKε-deficient cells die rapidly, prematurely, and exclusively by enhanced NLRP3-driven pyroptosis. Even infection with the RIPK1-activating pathogen, Yersinia pseudotuberculosis, results in enhanced RIPK1-caspase-8 activation and enhanced secondary NLRP3 activation. Mechanistically, TBK1/IKKε control endosomal traffic, and their loss disrupts endosomal homeostasis, thereby signaling cell stress. This results in premature NLRP3 activation even upon sensing "signal 2" alone, without the obligatory "signal 1." Collectively, TBK1/IKKε emerge as a central brake in limiting death-induced inflammation by both RIPK1 and NLRP3 death-inducing pathways.

DOI: https://doi.org/10.1126/sciadv.adq1047
bioRxiv. 2025 Feb 17. pii: 2025.02.13.638189. [Epub ahead of print]

Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection.

Víctor R Vázquez Marrero, Jessica Doerner, Kimberly A Wodzanowski, Jenna Zhang, Allyson Lu, Frankie D Boyer, Isabel Vargas, Suzana Hossain, Karly B Kammann, Madison V Dresler, Sunny Shin.

The innate immune system relies on pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and guard proteins to monitor pathogen disruption of host cell processes. How different immune cell types engage PRR- and guard protein-dependent defenses in response to infection is poorly understood. Here, we show that macrophages and dendritic cells (DCs) respond in distinct ways to bacterial virulence activities. In macrophages, the bacterial pathogen Legionella pneumophila deploys its Dot/Icm type IV secretion system (T4SS) to deliver effector proteins that facilitate its robust intracellular replication. In contrast, T4SS activity triggers rapid DC death that potently restricts Legionella replication within this cell type. Intriguingly, we found that infected DCs exhibit considerable heterogeneity at the single cell level. Initially, a subset of DCs activate caspase-11 and NLRP3 inflammasome-dependent pyroptosis and release IL-1 β early during infection. At later timepoints, a separate DC population undergoes apoptosis driven by T4SS effectors that block host protein synthesis, thereby depleting the levels of the pro-survival proteins Mcl-1 and cFLIP. Together, pyroptosis and effector-triggered apoptosis robustly restrict Legionella replication in DCs. Collectively, our work suggests a model where Mcl-1 and cFLIP guard host translation in DCs, and that macrophages and DCs distinctly employ innate immune sensors and guard proteins to mount divergent responses to Legionella infection.

DOI: https://doi.org/10.1101/2025.02.13.638189
Cell Host Microbe. 2025 Feb 26. pii: S1931-3128(25)00056-3. [Epub ahead of print]

Cross-kingdom-mediated detection of intestinal protozoa through NLRP6.

Nathaniel J Winsor, Giuliano Bayer, Ojas Singh, Jeremy K Chan, Lu Yi Li, Brandon Y Lieng, Elisabeth Foerster, Ana Popovic, Boyan K Tsankov, Heather Maughan, Paul Lemire, Elaine Tam, Catherine Streutker, Lina Chen, Stacey L Heaver, Ruth E Ley, John Parkinson, J Rafael Montenegro-Burke, George M H Birchenough, Dana J Philpott, Stephen E Girardin.

  Intestinal protists are detected by the host innate immune system through mechanisms that remain poorly understood. Here, we demonstrate that Tritrichomonas protozoa induce thickening of the colonic mucus in an NLRP6-, ASC-, and caspase-11-dependent manner, consistent with the activation of sentinel goblet cells. Mucus growth is recapitulated with cecal extracts from Tritrichomonas-infected mice but not purified protozoa, suggesting that NLRP6 may detect infection-induced microbial dysbiosis. In agreement, Tritrichomonas infection causes a shift in the microbiota with the expansion of Bacteroides and Prevotella, and untargeted metabolomics reveals a dramatic increase in several classes of metabolites, including sphingolipids. Finally, using a combination of gnotobiotic mice and ex vivo mucus analysis, we demonstrate that wild-type, but not sphingolipid-deficient, B. thetaiotaomicron is sufficient to induce NLRP6-dependent sentinel goblet cell function, with the greatest effect observed in female mice. Thus, we propose that NLRP6 is a sensor of intestinal protozoa infection through monitoring microbial sphingolipids.

Keywords:  Bacteroides; NLRP6; Tritrichomonas; goblet cells; inflammasomes; mucosal immunity; protozoan infection; sphingolipids

DOI:  https://doi.org/10.1016/j.chom.2025.02.008
Sci Adv. 2025 Feb 28. 11(9): eadu7985

Norovirus co-opts NINJ1 for selective protein secretion.

Jaewon Song, Li Zhang, Seokoh Moon, Ariana Fang, Guoxun Wang, Newsha Gheshm, Skylar A Loeb, Paul Cao, Joselynn R Wallace, Mia Madel Alfajaro, Madison S Strine, Wandy L Beatty, Amanda M Jamieson, Robert C Orchard, Bridget A Robinson, Timothy J Nice, Craig B Wilen, Anthony Orvedahl, Tiffany A Reese, Sanghyun Lee.

Plasma membrane rupture by Ninjurin-1 (NINJ1) executes programmed cell death, releasing large cellular damage-associated molecular patterns (DAMPs). However, the regulation and selectivity of NINJ1-mediated DAMP release remain unexplored. Here, we uncover that murine norovirus (MNoV) strategically co-opts NINJ1 to selectively release the intracellular viral protein NS1, while NINJ1-mediated plasma membrane rupture simultaneously bulk-releases various cellular DAMPs. Host caspase-3 cleaves the precursor NS1/2, leading to NS1 secretion via an unconventional pathway. An unbiased CRISPR screen identifies NINJ1 as an essential factor for NS1 secretion. During infection, NINJ1 is recruited to the viral replication site, where it oligomerizes and forms speckled bodies, directly interacting with NS1. Subsequent mutagenesis studies identify critical amino acid residues of NS1 necessary for its interaction with NINJ1 and selective secretion. Genetic ablation or pharmaceutical inhibition of caspase-3 inhibits oral MNoV infection in mice. This study underscores the co-option of NINJ1 for controlled release of an intracellular viral protein.

DOI: https://doi.org/10.1126/sciadv.adu7985
Front Immunol. 2025 ;16 1516120

Caspase-11 and NLRP3 exacerbate systemic Klebsiella infection through reducing mitochondrial ROS production.

Yuqi Zhou, Zhuodong Chai, Ankit Pandeya, Ling Yang, Yan Zhang, Guoying Zhang, Congqing Wu, Zhenyu Li, Yinan Wei.

   Introduction: Klebsiella pneumoniae is a Gram-negative bacterium and the third most commonly isolated microorganism in blood cultures from septic patients. Despite extensive research, the mechanisms underlying K. pneumoniae-induced sepsis and its pathogenesis remain unclear. Acute respiratory failure is a leading cause of mortality in systemic K. pneumoniae infections, highlighting the need to better understand the host immune response and bacterial clearance mechanisms.
Method: To investigate the impact of K. pneumoniae infection on organ function and immune response, we utilized a systemic infection model through intraperitoneal injection in mice. Bacterial loads in key organs were quantified, and lung injury was assessed. Survival analysis was performed in wild-type (WT) and gene deficient mice. Mitochondrial damage and reactive oxygen species (ROS) production, as well as cytokine levels were measured in macrophages isolated from these mice to evaluate their contribution to bacterial clearance capacity.
Results: Our findings demonstrate that K. pneumoniae systemic infection results in severe lung injury and significant bacterial accumulation in multiple organs, with the highest burden in the lungs. Deficiency of caspase-11 or NLRP3 led to prolonged survival, a reduction in pulmonary bacterial load, increased blood oxygen levels, and decreased IL-6 levels in the lungs compared to WT controls. Furthermore, caspase-11- and NLRP3-deficient macrophages exhibited elevated mitochondrial ROS production in response to K. pneumoniae, which correlated with more effective bacterial clearance.
Discussion: These results suggest that caspase-11 and NLRP3 contribute to K. pneumoniae-induced sepsis by impairing mitochondrial function and reducing ROS production in macrophages, thereby compromising bacterial clearance. The observed reduction in lung injury and increased survival in caspase-11- and NLRP3-deficient mice indicate that targeting these pathways may offer potential therapeutic strategies to improve host defense against systemic K. pneumoniae infection.

Keywords:  Klebsiella; NLRP3; ROS; caspase-11; inflammasome; pneumonia; sepsis

DOI:  https://doi.org/10.3389/fimmu.2025.1516120
Sci Adv. 2025 Mar 07. 11(10): eadt9027

LPS binding caspase activation and recruitment domains (CARDs) are bipartite lipid binding modules.

Anh B Cao, Pascal Devant, Chengliang Wang, Mengyu Sun, Stephanie N Kennedy, Weiyi Ma, Jianbin Ruan, Jonathan C Kagan.

Caspase-11 is an innate immune pattern recognition receptor (PRR) that detects cytosolic bacterial lipopolysaccharides (LPS) through its caspase activation and recruitment domain (CARD). Caspase-11 also detects eukaryotic (i.e., self) lipids. This observation raises the question of whether common or distinct mechanisms govern caspase interactions with self- and nonself-lipids. In this study, using biochemical, computational, and cell-based assays, we report that the caspase-11 CARD functions as a bipartite lipid-binding module. Distinct regions within the CARD bind to phosphate groups and long acyl chains of self- and nonself-lipids. Self-lipid binding capability is conserved across numerous caspase-11 homologs and orthologs. The symmetry in self- and nonself-lipid detection mechanisms enabled us to engineer an LPS-binding domain de novo, using an ancestral CARD-like domain present in the fish Amphilophus citrinellus. These findings offer insights into the molecular basis of LPS recognition by caspase-11 and highlight the fundamental and likely inseparable relationship between self and nonself discrimination.

DOI: https://doi.org/10.1126/sciadv.adt9027
bioRxiv. 2025 Feb 23. pii: 2025.02.18.638923. [Epub ahead of print]

The immunometabolic topography of tuberculosis granulomas governs cellular organization and bacterial control.

Erin F McCaffrey, Alea C Delmastro, Isobel Fitzhugh, Jolene S Ranek, Sarah Douglas, Joshua M Peters, Christine Camacho Fullaway, Marc Bosse, Candace C Liu, Craig Gillen, Noah F Greenwald, Sarah Anzick, Craig Martens, Seth Winfree, Yunhao Bai, Cameron Sowers, Mako Goldston, Alex Kong, Potchara Boonrat, Carolyn L Bigbee, Roopa Venugopalan, Pauline Maiello, Edwin Klein, Mark A Rodgers, Charles A Scanga, Philana Ling Lin, Denise Kirschner, Sarah Fortune, Bryan D Bryson, J Russell Butler, Joshua T Mattila, JoAnne L Flynn, Michael Angelo.

Despite being heavily infiltrated by immune cells, tuberculosis (TB) granulomas often subvert the host response to Mycobacterium tuberculosis (Mtb) infection and support bacterial persistence. We previously discovered that human TB granulomas are enriched for immunosuppressive factors typically associated with tumor-immune evasion, raising the intriguing possibility that they promote tolerance to infection. In this study, our goal was to identify the prime drivers for establishing this tolerogenic niche and to determine if the magnitude of this response correlates with bacterial persistence. To do this, we conducted a multimodal spatial analysis of 52 granulomas from 16 non-human primates (NHP) who were infected with low dose Mtb for 9-12 weeks. Notably, each granuloma's bacterial burden was individually quantified allowing us to directly ask how granuloma spatial structure and function relate to infection control. We found that a universal feature of TB granulomas was partitioning of the myeloid core into two distinct metabolic environments, one of which is hypoxic. This hypoxic environment associated with pathologic immune cell states, dysfunctional cellular organization of the granuloma, and a near-complete blockade of lymphocyte infiltration that would be required for a successful host response. The extent of these hypoxia-associated features correlated with worsened bacterial burden. We conclude that hypoxia governs immune cell state and organization within granulomas and is a potent driver of subverted immunity during TB.

DOI: https://doi.org/10.1101/2025.02.18.638923
Cell Host Microbe. 2025 Feb 20. pii: S1931-3128(25)00051-4. [Epub ahead of print]

Mitochondria sense bacterial lactate and drive release of neutrophil extracellular traps.

Ashley D Wise, Eden G TenBarge, Jessica D C Mendonça, Ellie C Mennen, Sarah R McDaniel, Callista P Reber, Bailey E Holder, Madison L Bunch, Eva Belevska, Madalyn G Marshall, Nicole M Vaccaro, Christian R Blakely, Dinesh H Wellawa, Jennifer Ferris, Jessica R Sheldon, Jeffry D Bieber, Jeremiah G Johnson, Lindsey R Burcham, Andrew J Monteith.

  Neutrophils induce oxidative stress, creating a harsh phagosomal environment. However, Staphylococcus aureus can survive these conditions, requiring neutrophils to deploy mechanisms that sense bacterial persistence. We find that staphylococcal lactate is a metabolic danger signal that triggers neutrophil extracellular trap release (NETosis). Neutrophils coordinate mitochondria in proximity to S. aureus-containing phagosomes, allowing transfer of staphylococcal lactate to mitochondria where it is rapidly converted into pyruvate and causes mitochondrial reactive oxygen species, a precursor to NETosis. Similar results were observed in response to phylogenetically distinct bacteria, implicating lactate accumulation as a broad signal triggering NETosis. Furthermore, patients with systemic lupus erythematosus (SLE) are more susceptible to bacterial infections. We find that SLE neutrophils cannot sense bacterial lactate impairing their capacity to undergo NETosis upon S. aureus infection but initiate aberrant NETosis triggered by apoptotic debris. Thus, neutrophils adapt mitochondria as sensory organelles that detect bacterial metabolic activity and dictate downstream antibacterial processes.

Keywords:  NETosis; Staphylococcus aureus; lactate; lactate dehydrogenase; mitochondria; neutrophil extracellular traps; neutrophils; phagosome; reverse electron trasport; systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.chom.2025.02.003
Front Immunol. 2025 ;16 1529756

Epigenetic regulation of transcription factors involved in NLRP3 inflammasome and NF-kB signaling pathways.

John Kaszycki, Minji Kim.

  The NLRP3 inflammasome and NF-κB signaling pathways play crucial roles in orchestrating inflammation and immune defense. This review explores the intricate relationship between these pathways and epigenetic regulation, a field of growing importance in understanding immune responses. Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), significantly influence the activity of genes involved in these pathways, thereby modulating inflammatory responses. The review provides a comprehensive overview of current research on how epigenetic mechanisms interact with and regulate the NLRP3 inflammasome and NF-κB signaling pathways. It delves into advanced epigenetic concepts such as RNA modifications and 3D genome organization, and their impact on immune regulation. Furthermore, the implications of these findings for developing novel therapeutic strategies targeting epigenetic regulators in inflammatory diseases are discussed. By synthesizing recent advancements in this rapidly evolving field, this review underscores the critical role of epigenetic regulation in immune signaling and highlights the potential for epigenetic-based therapies in treating a wide range of inflammatory conditions, including autoimmune disorders and cancer.

Keywords:  NF-κB signaling; NLRP3 inflammasome; chromatin remodeling; epigenetics; inflammation

DOI:  https://doi.org/10.3389/fimmu.2025.1529756
Nat Commun. 2025 Mar 04. 16(1): 2184

Methionine metabolite spermidine inhibits tumor pyroptosis by enhancing MYO6-mediated endocytosis.

Jiawei Wu, Cong Ding, Chuqing Zhang, Zhimin Xu, Zhenji Deng, Hanmiao Wei, Tingxiang He, Liufen Long, Linglong Tang, Jun Ma, Xiaoyu Liang.

The connection between amino acid metabolism and pyroptosis remains elusive. Herein, we screen the effect of individual amino acid on pyroptosis and identify that methionine inhibits GSDME-mediated pyroptosis. Mechanistic analyses unveil that MYO6, a unique actin-based motor protein, bridges the GSDME N-terminus (GSDME-NT) and the endocytic adaptor AP2, mediating endolysosomal degradation of GSDME-NT. This degradation is increased by the methionine-derived metabolite spermidine noncanonically by direct binding to MYO6, which enhances MYO6 selectivity for GSDME-NT. Moreover, combination targeted therapies using dietary or pharmacological inhibition in methionine-to-spermidine metabolism in the tumor promotes pyroptosis and anti-tumor immunity, leading to a stronger tumor-suppressive effect in in vivo models. Clinically, higher levels of tumor spermidine and expression of methionine-to-spermidine metabolism-related gene signature predict poorer survival. Conclusively, our research identifies an unrecognized mechanism of pyroptotic resistance mediated by methionine-spermidine metabolic axis, providing a fresh angle for cancer treatment.

DOI: https://doi.org/10.1038/s41467-025-57511-4