bims-inflin 2025-02-02 papers

bims-inflin

Biomed News

on Inflammasome and infection

Issue of 2025–02–02
ten papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

Activation of the conserved Hippo kinases by inflammasome-triggered proteolytic cleavage controls programmed cell death in macrophages.
Guards and decoys: RIPoptosome and inflammasome pathway regulators of bacterial effector-triggered immunity.
Diverse autoinhibitory mechanisms of FIIND-containing proteins: Insight into regulation of NLRP1 and CARD8 inflammasome.
Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice.
CARD domains mediate anti-phage defence in bacterial gasdermin systems.
Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection.
Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel.
Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4.
Legionella pneumophila subverts the antioxidant defenses of its amoeba host Acanthamoeba castellanii.
Executioner caspases degrade essential mediators of pathogen-host interactions to inhibit growth of intracellular Listeria monocytogenes.

Proc Natl Acad Sci U S A. 2025 Feb 04. 122(5): e2418613122

Activation of the conserved Hippo kinases by inflammasome-triggered proteolytic cleavage controls programmed cell death in macrophages.

Yu-Ting Su, Sydney M Quagliato, Brendyn M St Louis, Mohamed H Abdelaziz, Yuan He, Devanand Bondage, Stephanie S Lehman, Pei-Chung Lee.

  The mammalian Hippo kinases, MST1 and MST2, regulate organ development and suppress tumor formation by balancing cell proliferation and death. In macrophages, inflammasomes detect molecular patterns from invading pathogens or damaged host cells and trigger programmed cell death. In addition to lytic pyroptosis, the signatures associated with apoptosis are induced by inflammasome activation, but how the inflammasomes coordinate different cell death processes remains unclear. Here, we identify the crucial role of MST1/2 in inflammasome-triggered cell death. Macrophages proteolytically convert full-length MST1/2 into the MST1/2 N-terminal fragments (MST1/2-NT) when the NLRC4 inflammasome detects flagellin from the pathogenic bacterium, Legionella pneumophila. Activation of the NLRP3 inflammasome by the damage-associated molecular pattern, extracellular ATP, also produces MST1/2-NT. Caspase-1, the protease activated by these inflammasomes, directly cleaves MST1/2, and blockage of caspase-1 inhibits MST1/2-NT production in macrophages challenged with L. pneumophila. Importantly, MST1/2-NT production is critical for macrophages to trigger a set of death processes associated with apoptosis upon inflammasome activation and knocking out Mst1/2 causes dysregulated gasdermin protein cleavage for pyroptotic death. Furthermore, macrophages lacking MST1/2 have increased susceptibility to virulent L. pneumophila, revealing that the Hippo kinases are important restriction factors against the pathogen. These findings demonstrate that proteolytic cleavage of MST1/2 induced by inflammatory stimuli is an immune pathway to regulate programmed cell death in macrophages and uncover a unique link between the tumor-suppressive Hippo kinases and the inflammasomes in innate immunity.

Keywords:  GSDME; STK3; STK4; pattern recognition receptors; type IV secretion

DOI:  https://doi.org/10.1073/pnas.2418613122
PLoS Pathog. 2025 Jan;21(1): e1012884

Guards and decoys: RIPoptosome and inflammasome pathway regulators of bacterial effector-triggered immunity.

Haleema Sadia Malik, James B Bliska.

Virulent microbes produce proteins that interact with host cell targets to promote pathogenesis. For example, virulent bacterial pathogens have proteins called effectors that are typically enzymes and are secreted into host cells. To detect and respond to the activities of effectors, diverse phyla of host organisms evolved effector-triggered immunity (ETI). In ETI, effectors are often sensed indirectly by detection of their virulence activities in host cells. ETI mechanisms can be complex and involve several classes of host proteins. Guards monitor the functional or physical integrity of another host protein, the guardee or decoy, and become activated to initiate an immune response when the guardee or decoy is modified or disrupted by an effector. A guardee typically has an intrinsic anti-pathogen function and is the intended target of an effector. A decoy structurally mimics a host protein that has intrinsic anti-pathogen activity and is unintentionally targeted by an effector. A decoy can be an individual protein, or a protein domain integrated into a guard. Here, we review the origins of ETI and focus on 5 mechanisms, in which the key steps of a pathway can include activation of a caspase by a RIPoptosome or inflammasome, formation of pores in the plasma membrane, release of cytokines and ending in cell death by pyroptosis. Survey of the 5 mechanisms, which have been shown to be host protective in mouse models of bacterial infection, reveal how distinct regulators of RIPoptosome or inflammasome pathways can act as guards or integrated decoys to trigger ETI. Common themes are highlighted and the limited mechanistic understanding of ETI bactericidal activity is discussed.

DOI: https://doi.org/10.1371/journal.ppat.1012884
PLoS Pathog. 2025 Jan;21(1): e1012877

Diverse autoinhibitory mechanisms of FIIND-containing proteins: Insight into regulation of NLRP1 and CARD8 inflammasome.

Jingfan Zhou, Chengrong Liu, Xin Wang, Zhenshan Liu, Zizhen Ming, Yonggang Wang, Chunxia Wang, Qiming Liang.

Function-to-find domain (FIIND)-containing proteins, including NLRP1 and CARD8, are vital components of the inflammasome signaling pathway, critical for the innate immune response. These proteins exist in various forms due to autoproteolysis within the FIIND domain, resulting in full-length (FL), cleaved N-terminal (NT), and cleaved C-terminal (CT) peptides, which form autoinhibitory complexes in the steady state. However, the detailed mechanism remains elusive. Here, we found that both NLRP1 paralogs and CARD8 form two conserved autoinhibitory complexes involving NT-CT interactions and FL-CT interactions, but with distinct mechanisms. Specifically, the Linker3 region located between LRR and FIIND in murine NLRP1b (mNLRP1b) plays an essential role in forming the NT-CT autoinhibitory complexes, while the ZU5 of rat NLRP1 (rNLRP1) and CARD8 mediates their NT-CT interaction. In addition, we explored the involvement of the cellular protease dipeptidyl peptidases 9 (DPP9) in these complexes, revealing differential interactions and the significance of domain structure. Besides the FL-DPP9-CT complex, DPP9 interacts with NTs of mNLRP1b, rNLRP1, and CARD8 through their ZU5 subdomains, forming NT-DPP9-CT complex; however, DPP9 cannot bind to NTs of hNLRP1. Further functional assay indicated that although DPP9 is involved in the NT-CT complex of rodent NLRP1 and CARD8, it does not influence the inhibitory activity of NT on CT. Our study enhanced the understanding of the regulatory functions of FIIND-containing proteins in inflammasome autoinhibition and activation and underscored the complexity of their interactions within the immune response.

DOI: https://doi.org/10.1371/journal.ppat.1012877
Nat Commun. 2025 Jan 15. 16(1): 699

Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice.

Sung-Hyun Yoon, Chae Youn Kim, Eunju Lee, Changjun Lee, Kyung-Seo Lee, Jaeho Lee, Hana Park, Bokeum Choi, Inhwa Hwang, Junhan Kim, Tae-Gyun Kim, Junghyun Son, Young-Min Hyun, Seunghee Hong, Je-Wook Yu.

Blood-brain barrier (BBB) disintegration is a key contributor to neuroinflammation; however, the biological processes governing BBB permeability under physiological conditions remain unclear. Here, we investigate the role of NLRP3 inflammasome in BBB disruption following peripheral inflammatory challenges. Repeated intraperitoneal lipopolysaccharide administration causes NLRP3-dependent BBB permeabilization and myeloid cell infiltration into the brain. Using a mouse model with cell-specific hyperactivation of NLRP3, we identify microglial NLRP3 activation as essential for peripheral inflammation-induced BBB disruption. Conversely, NLRP3 and microglial gasdermin D (GSDMD) deficiency markedly attenuates lipopolysaccharide-induced BBB breakdown. Notably, IL-1β is not required for NLRP3-GSDMD-mediated BBB disruption. Instead, microglial NLRP3-GSDMD axis upregulates CXCL chemokines and matrix metalloproteinases around BBB via producing GDF-15, promoting the recruitment of CXCR2-containing neutrophils. Inhibition of neutrophil infiltration and matrix metalloproteinase activity significantly reduces NLRP3-mediated BBB impairment. Collectively, these findings reveal the important role of NLRP3-driven chemokine production in BBB disintegration, suggesting potential therapeutic targets to mitigate neuroinflammation.

DOI: https://doi.org/10.1038/s41467-025-56097-1
Nature. 2025 Jan 29.

CARD domains mediate anti-phage defence in bacterial gasdermin systems.

Tanita Wein, Adi Millman, Katharina Lange, Erez Yirmiya, Romi Hadary, Jeremy Garb, Sarah Melamed, Gil Amitai, Orly Dym, Felix Steinruecke, Aidan B Hill, Philip J Kranzusch, Rotem Sorek.

Caspase recruitment domains (CARDs) and pyrin domains are important facilitators of inflammasome activity and pyroptosis1. Following pathogen recognition by nucleotide binding-domain, leucine-rich, repeat-containing (NLR) proteins, CARDs recruit and activate caspases, which, in turn, activate gasdermin pore-forming proteins to induce pyroptotic cell death2. Here we show that CARD domains are present in defence systems that protect bacteria against phage. The bacterial CARD domain is essential for protease-mediated activation of certain bacterial gasdermins, which promote cell death once phage infection is recognized. We further show that multiple anti-phage defence systems use CARD domains to activate a variety of cell death effectors, and that CARD domains mediate protein-protein interactions in these systems. We find that these systems are triggered by a conserved immune-evasion protein used by phages to overcome the bacterial defence system RexAB3, demonstrating that phage proteins inhibiting one defence system can activate another. Our results suggest that CARD domains represent an ancient component of innate immune systems conserved from bacteria to humans, and that CARD-dependent activation of gasdermins is shared in organisms across the tree of life.

DOI: https://doi.org/10.1038/s41586-024-08498-3
PLoS Pathog. 2025 Jan;21(1): e1012858

Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection.

Souradeepa Ghosh, Krishna Vamshi Chigicherla, Shirin Dasgupta, Yasuyuki Goto, Budhaditya Mukherjee.

Despite the withdrawal of pentavalent-antimonials in treating Visceral leishmaniasis from India, recent clinical isolates of Leishmania donovani (LD) exhibit unresponsiveness towards pentavalent-antimony (LD-R). This antimony-unresponsiveness points towards a genetic adaptation that underpins LD-R's evolutionary persistence and dominance over sensitive counterparts (LD-S). This study highlights how LD evolutionarily tackled antimony exposure and gained increased potential of scavenging host-iron within its parasitophorous vacuoles (PV) to support its aggressive proliferation. Even though anti-leishmanial activity of pentavalent antimonials relies on triggering oxidative outburst, LD-R exhibits a surprising strategy of promoting reactive oxygen species (ROS) generation in infected macrophages. An inherent metabolic shift from glycolysis to Pentose Phosphate shunt allows LD-R to withstand elevated ROS by sustaining heightened levels of NADPH. Elevated ROS levels on the other hand trigger excess iron production, and LD-R capitalizes on this surplus iron by selectively reshuffling macrophage-surface iron exporter, Ferroportin, around its PV thereby gaining a survival edge as a heme-auxotroph. Higher iron utilization by LD-R leads to subsequent iron insufficiency, compensated by increased erythrophagocytosis through the breakdown of SIRPα-CD47 surveillance, orchestrated by a complex interplay of two proteases, Furin and ADAM10. Understanding these mechanisms is crucial for managing LD-R-infections and their associated complications like severe anemia, and may also provide valuable mechanistic insights into understanding drug unresponsiveness developed in other intracellular pathogens that rely on host iron.

DOI: https://doi.org/10.1371/journal.ppat.1012858
Nat Commun. 2025 Jan 24. 16(1): 985

Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel.

Yanhong Xing, Meng-Meng Wang, Feifei Zhang, Tianli Xin, Xinyan Wang, Rong Chen, Zhongheng Sui, Yawei Dong, Dongxue Xu, Xingyu Qian, Qixia Lu, Qingqing Li, Weijie Cai, Meiqin Hu, Yuqing Wang, Jun-Li Cao, Derong Cui, Jiansong Qi, Wuyang Wang.

Lysosomes are best known for their roles in inflammatory responses by engaging in autophagy to remove inflammasomes. Here, we describe an unrecognized role for the lysosome, showing that it finely controls macrophage inflammatory function by manipulating the lysosomal Fe2+-prolyl hydroxylase domain enzymes (PHDs)-NF-κB-interleukin 1 beta (IL1B) transcription pathway that directly links lysosomes with inflammatory responses. TRPML1, a lysosomal cationic channel, is activated secondarily to ROS elevation upon inflammatory stimuli, which in turn suppresses IL1B transcription, thus limiting the excessive production of IL-1β in macrophages. Mechanistically, the suppression of IL1B transcription caused by TRPML1 activation results from its modulation on the release of lysosomal Fe2+, which subsequently activates PHDs. The activated PHDs then represses transcriptional activity of NF-κB, ultimately resulting in suppressed IL1B transcription. More importantly, in vivo stimulation of TRPML1 ameliorates multiple clinical signs of Dextran sulfate sodium-induced colitis in mice, suggesting TRPML1 has potential in treating inflammatory bowel disease.

DOI: https://doi.org/10.1038/s41467-025-56403-x
FASEB J. 2025 Jan 15. 39(1): e70301

Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4.

Hanna Englert, Chandini Rangaswamy, Giuliano A Kullik, Mylène Divivier, Josephine Göbel, Irm Hermans-Borgmeyer, Uwe Borgmeyer, Kerri A Mowen, Manu Beerens, Maike Frye, Reiner K Mailer, Mathias Gelderblom, Evi X Stavrou, Roger J S Preston, Stefan W Schneider, Tobias A Fuchs, Thomas Renné.

  Neutrophils are peripheral blood-circulating leukocytes that play a pivotal role in host defense against bacterial pathogens which upon activation, they release web-like chromatin structures called neutrophil extracellular traps (NETs). Here, we analyzed and compared the importance of myeloid differentiation factor 88 (MYD88), peptidyl arginine deiminase 4 (PAD4), and gasdermin D (GSDMD) for NET formation in vivo following sepsis and neutrophilia challenge. Injection of lipopolysaccharide (LPS)/E. coli or the transgenic expression of granulocyte colony-stimulating factor (G-CSF), each induced NET-mediated lethal vascular occlusions in mice with combined genetic deficiency in Dnase1 and Dnase1l3 (D1/D1l3-/-). In accordance with the signaling of toll-like receptors, Myd88/D1/D1l3-/- animals were protected from the formation of lethal intravascular NETs during septic conditions. However, this protection was not observed during neutrophilia. It was unexpected to find that both Gsdmd/D1/D1l3-/- and Pad4/D1/D1l3-/- mice were fully capable of forming NETs upon LPS/E.coli challenge. Sepsis equally triggered a similar inflammatory response in these mice characterized by formation of DNA-rich thrombi, vessel occlusions, and mortality from pulmonary embolism, compared to D1/D1l3-/- mice. Pharmacologic GSDMD inhibitors did not reduce PMA-stimulated NET formation in ex vivo models either. Similarly, neither Pad4 nor GSDMD deficiency affected intravascular occlusive NET formation upon neutrophilia challenge. The magnitude of NET production, multi-organ damage, and lethality were comparable to those observed in challenged control mice. In conclusion, our data indicate that NET formation during experimental sepsis and neutrophilia is regulated by distinct stimulus-dependent pathways that may be independent of canonical PAD4 and GSDMD.

Keywords:  GSDMD; PAD4; immunothrombosis; inflammation; neutrophil extracellular traps; vascular biology

DOI:  https://doi.org/10.1096/fj.202402514R
Curr Res Microb Sci. 2025 ;8 100338

Legionella pneumophila subverts the antioxidant defenses of its amoeba host Acanthamoeba castellanii.

Alban Hay, Willy Aucher, Romain Pigeault, Joanne Bertaux, Alexandre Crépin, Quentin Blancart Remaury, Yann Héchard, Ascel Samba-Louaka, Romain Villéger.

  Legionella pneumophila, the causative agent of Legionnaires' disease, interacts in the environment with free-living amoebae that serve as replicative niches for the bacteria. Among these amoebae, Acanthamoeba castellanii is a natural host in water networks and a model commonly used to study the interaction between L. pneumophila and its host. However, certain crucial aspects of this interaction remain unclear. One such aspect is the role of oxidative stress, with studies focusing on reactive oxygen species (ROS) production by the host and putting less emphasis on the involvement of the host's antioxidant defenses during the infectious process. In this study, we propose to examine the consequences of infection with L. pneumophila wild-type or with an isogenic ΔdotA mutant strain, which is unable to replicate intracellularly, on A. castellanii. For this purpose, we looked at the host ROS levels, host antioxidant defense transcripts, and metabolites linked to the amoeba's antioxidant defenses. It is known that L. pneumophila WT can block the activation of NADPH oxidase as soon as it enters the macrophage and suppress ROS production compared to ΔdotA mutant strain. In addition, it has been shown in macrophages that L. pneumophila WT decreases ROS at 24 h p.i.; here we confirm this result in amoebae and suggest that this decrease could be partly explained by L. pneumophila differentially regulated host antioxidant defense transcripts at 6 h p.i.. We also explored the metabolome of A. castellanii infected or not with L. pneumophila. Among the 617 metabolites identified, four with reduced abundances during infection may be involved in antioxidant responses. This study suggests that L. pneumophila could hijack the host's antioxidant defenses during its replication to maintain a reduced level of ROS.

Keywords:  Acanthamoeba castellanii; Antioxidant defenses; Host-pathogen interaction; Legionella pneumophila; Reactive oxygen species; T4SS dependent

DOI:  https://doi.org/10.1016/j.crmicr.2024.100338
Cell Death Dis. 2025 Jan 30. 16(1): 55

Executioner caspases degrade essential mediators of pathogen-host interactions to inhibit growth of intracellular Listeria monocytogenes.

Marilyne Lavergne, Raffael Schaerer, Sara De Grandis, Safaa Bouheraoua, Oluwadamilola Adenuga, Tanja Muralt, Tiffany Schaerer, Léa Chèvre, Alessandro Failla, Patricia Matthey, Michael Stumpe, Dieter Kressler, Pierre-Yves Mantel, Michael Walch.

Cell death mediated by executioner caspases is essential during organ development and for organismal homeostasis. The mechanistic role of activated executioner caspases in antibacterial defense during infections with intracellular bacteria, such as Listeria monocytogenes, remains elusive. Cell death upon intracellular bacterial infections is considered altruistic to deprive the pathogens of their protective niche. To establish infections in a human host, Listeria monocytogenes deploy virulence mediators, including membranolytic listeriolysin O (LLO) and the invasion associated protein p60 (Iap), allowing phagosomal escape, intracellular replication and cell-to-cell spread. Here, by means of chemical and genetical modifications, we show that the executioner caspases-3 and -7 efficiently inhibit growth of intracellular Listeria monocytogenes in host cells. Comprehensive proteomics revealed multiple caspase-3 substrates in the Listeria secretome, including LLO, Iap and various other proteins crucially involved in pathogen-host interactions. Listeria secreting caspase-uncleavable LLO or Iap gained significant growth advantage in epithelial cells. With that, we uncovered an underappreciated defense barrier and a non-canonical role of executioner caspases to degrade virulence mediators, thus impairing intracellular Listeria growth.

DOI: https://doi.org/10.1038/s41419-025-07365-x