bims-inflin 2024-11-24 papers

bims-inflin

Biomed News

on Inflammasome and infection

Issue of 2024–11–24
nine papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

Role of inflammasomes in Toxoplasma and Plasmodium infections.
IL-33 deficiency inhibits Toxoplasma gondii infection by promoting NLRP3 inflammasome.
TLR priming licenses NAIP inflammasome activation by immunoevasive ligands.
Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring.
PDCD6 regulates lactate metabolism to modulate LC3-associated phagocytosis and antibacterial defense.
Neutrophil extracellular traps facilitate liver inflammation/fibrosis progression by entering macrophages and triggering AIM2 inflammasome-dependent pyroptosis.
Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation.
A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control.
Gasdermin D unlocks metabolic pathways to enhance tissue regeneration.

Parasit Vectors. 2024 Nov 15. 17(1): 466

Role of inflammasomes in Toxoplasma and Plasmodium infections.

Zhi-Xin Wang, Wan-Jun Jiao, Yong Yang, Hong-Li Liu, Hai-Long Wang.

   BACKGROUND: The detection of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) by multimeric protein complexes, known as inflammasomes, triggers an inflammatory response, which is a critical component of the innate immune system. This inflammatory response plays a pivotal role in host resistance against parasitic infections, presenting a significant global health challenge.
METHODS: We systematically searched for relevant articles from the Pubmed and the Web of Science database to summarize current insights into how inflammasomes function in preventing infections caused by the apicomplexan parasites Toxoplasma and Plasmodium.
RESULTS: In vivo and in vitro studies have extensively explored inflammasomes such as the absent in melanoma 2 (AIM2), NLR family pyrin-containing protein 1 (NLRP1), NLRP3, and NLRP12 inflammasomes, alongside noncanonical inflammasomes, with particular emphasis on the NLRP1 and the NLRP3 inflammasome during Toxoplasma gondii infection or the AIM2 and the NLRP3 inflammasome at various stages of Plasmodium infection. Toxoplasma gondii interacts with inflammasomes to activate or inhibit immune responses.
CONCLUSIONS: Inflammasomes control parasite burden and parasite-induced cell death, contribute to immune recognition and inflammatory responses and thus influence apicomplexan parasite-associated pathogenesis and the severity of clinical outcomes. Hence, inflammasomes play crucial roles in the progression and outcomes of toxoplasmosis and malaria. A comprehensive understanding of how parasitic infections modulate inflammasome activity enhances insight into host immune responses against parasites.

Keywords:   Plasmodium ; T. gondii ; Infection; Inflammasomes

DOI:  https://doi.org/10.1186/s13071-024-06529-6
Parasitol Res. 2024 Nov 21. 123(11): 391

IL-33 deficiency inhibits Toxoplasma gondii infection by promoting NLRP3 inflammasome.

Yizhong Chen, Xiaoli He, Yuqin Chen, Rongzhao Zhang, Tengwen Zhang, Tao Zhang, Linqing Wu.

  NLRP3 inflammasome-mediated inflammatory responses play pivotal functions in innate immunity. However, its homeostatic regulation still needs to be better understood. Here we explore the effect and potential mechanism of IL-33 on NLRP3 inflammasome upon Toxoplasma gondii infection through a series of molecular biology and immunological experiments, including western blot, qRT-PCR, and ELISA. We demonstrated that T. gondii infection induces the expression of IL-33, and IL-33-deficient (IL-33-/-) mice exhibit longer survival time than wild-type (WT) mice upon T. gondii infection. IL-33 deficiency promotes the expression of NLRP3 and ASC and the secretion of IL-1β, while exogenous IL-33 inhibits NLRP3 inflammasome. Furthermore, T. gondii infection results in the M2 polarization of macrophages, exacerbated by exogenous IL-33, which also promotes the proliferation of T. gondii. These findings showed that IL-33 deficiency attenuates T. gondii infection by promoting NLRP3 inflammasome, advancing the understanding of the role of IL-33 in inflammation.

Keywords:   Toxoplasma gondii ; IL-33; Inflammation; Innate immunity; Macrophages; NLRP3 inflammasome; Polarization

DOI:  https://doi.org/10.1007/s00436-024-08414-8
Proc Natl Acad Sci U S A. 2024 Nov 26. 121(48): e2412700121

TLR priming licenses NAIP inflammasome activation by immunoevasive ligands.

James P Grayczyk, Luying Liu, Marisa S Egan, Emily Aunins, Meghan A Wynosky-Dolfi, Scott W Canna, Andy J Minn, Sunny Shin, Igor E Brodsky.

  NLR family, apoptosis inhibitory proteins (NAIPs) detect bacterial flagellin and structurally related components of bacterial type III secretion systems (T3SS), and recruit NLR family CARD domain containing protein 4 (NLRC4) and caspase-1 into an inflammasome complex that induces pyroptosis. NAIP/NLRC4 inflammasome assembly is initiated by the binding of a single NAIP to its cognate ligand, but a subset of bacterial flagellins or T3SS structural proteins are thought to evade NAIP/NLRC4 inflammasome sensing by not binding to their cognate NAIPs. Unlike other inflammasome components such as NLRP3, AIM2, or some NAIPs, NLRC4 is constitutively present in resting macrophages and not known to be induced by inflammatory signals. Here, we demonstrate that Toll-like receptor (TLR)-dependent p38 mitogen-activated protein kinase signaling up-regulates NLRC4 transcription and protein expression in murine macrophages, which licenses NAIP detection of evasive ligands. In contrast, TLR priming in human macrophages did not up-regulate NLRC4 expression, and human macrophages remained unable to detect NAIP-evasive ligands even following priming. Critically, ectopic expression of either murine or human NLRC4 was sufficient to induce pyroptosis in response to immunoevasive NAIP ligands, indicating that increased levels of NLRC4 enable the NAIP/NLRC4 inflammasome to detect these normally evasive ligands. Altogether, our data reveal that TLR priming tunes the threshold for the murine NAIP/NLRC4 inflammasome to enable inflammasome responses against immunoevasive or suboptimal NAIP ligands. These findings provide insight into species-specific TLR regulation of NAIP/NLRC4 inflammasome activation.

Keywords:  Inflammasome; NAIP; NLRC4; Type III secretion; pyroptosis

DOI:  https://doi.org/10.1073/pnas.2412700121
J Infect Dis. 2024 Nov 21. pii: jiae583. [Epub ahead of print]

Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring.

Ana Isabel Fernandes, Alexandre Jorge Pinto, Diogo Silvério, Ulrike Zedler, Carolina Ferreira, Iola F Duarte, Ricardo Silvestre, Anca Dorhoi, Margarida Saraiva.

  The diversity of Mycobacterium tuberculosis (Mtb) impacts the outcome of tuberculosis. We previously showed that Mtb isolates obtained from patients with severe disease induced low inflammasome activation and IL-1β production by infected macrophages. Here we questioned whether this differential modulation of macrophages by Mtb isolates depended on distinct metabolic reprogramming. We found that the macrophage metabolic landscape was similar regardless of the infecting Mtb isolate. Paralleling single-TLR activated macrophages, glycolysis inhibition during infection impaired IL-1β secretion. However, departing from TLR based models, in infected macrophages, IL-1β secretion was independent of mitochondrial metabolic changes and HIF-1α. Additionally, we found an unappreciated impact of a host metabolic inhibitor on the pathogen, and show that inflammasome activation and IL-1β production by macrophages require metabolically active bacteria. Our study highlights the potential confounding effect of host metabolic inhibitors on the pathogen and uncouples Mtb-inflammasome modulation from the host metabolic reprogramming.

Keywords:   Mycobacterium tuberculosis ; immunometabolism; inflammasome; macrophage

DOI:  https://doi.org/10.1093/infdis/jiae583
Nat Commun. 2024 Nov 23. 15(1): 10157

PDCD6 regulates lactate metabolism to modulate LC3-associated phagocytosis and antibacterial defense.

Lulu Sun, Sijin Wu, Hui Wang, Tianyu Zhang, Mengyu Zhang, Xuepeng Bai, Xiumei Zhang, Bingqing Li, Cai Zhang, Yan Li, Jun Zhou, Tianliang Li.

LC3-associated phagocytosis (LAP) is critical in host defense against invading pathogens, but the molecular mechanism for LAP activation is still unclear. Here, we find programmed cell death 6 (PDCD6) as a negative regulator of LAP. PDCD6 deficiency in mice and macrophages induces enhanced bactericidal activity and LAP formation. In parallel, lactate dehydrogenase A (LDHA) activity and lactate production is induced in macrophages challenged with bacteria, Zymosan or Pam3CSK4, while genetic ablation or pharmacological inhibition of LDHA reduces lactate levels and impairs bactericidal activity in vivo and in vitro. Mechanistically, PDCD6 interacts with LDHA to downregulate lactate metabolism, leading to reduced RUBCN lactylation at lysine33 (K33). By contrast, PDCD6-deficiency increases RUBCN lactylation, thereby promotes RUBCN interaction with VPS34, LAP formation, and protective responses. Our results thus suggest a PDCD6-LDHA-lactate-RUBCN axis of innate immunity regulation that may both contribute to protection from infectious diseases and serve as targets for therapeutic development.

DOI: https://doi.org/10.1038/s41467-024-54377-w
Cell Commun Signal. 2024 Nov 20. 22(1): 556

Neutrophil extracellular traps facilitate liver inflammation/fibrosis progression by entering macrophages and triggering AIM2 inflammasome-dependent pyroptosis.

Yu Zhang, Rong Wu, Xi Zhan, Xuan-Yi Wang, Lin-Wei Xiang, Ya-Qian Duan, Yan You, Jian-Bo Zhang, Rui Wu, Yun-Yuan Zhang, Liang Duan.

   BACKGROUND: Absent in melanoma 2 (AIM2) inflammasome-dependent pyroptosis and neutrophil extracellular traps (NETs) have been implicated in chronic liver disease (CLD). However, the specific intrahepatic cell type that undergoes AIM2 inflammasome-dependent pyroptosis and how their interaction augments hepatic inflammation/fibrosis remains unclear.
METHODS: The expression and correlation of AIM2 inflammasome-dependent pyroptosis-related indicators and NETs were analyzed in biopsy tissue and blood specimens from chronic hepatitis patients (CHs). Cell-based experiments were conducted to investigate their interaction. In vitro and in vivo experiments were used to analyze their effects on the progression of hepatic inflammation/fibrosis as well as their clinical importance.
RESULTS: Elevated levels of AIM2 inflammasome-dependent pyroptosis indicators and NETs were detected in biopsy tissue and blood specimens. Circulating NETs were positively correlated with pyroptosis-related indicators, and both were related with disease severity. Confocal imaging revealed that AIM2 was mainly localized to hepatic macrophages, indicating that hepatic macrophages were the major cell type that underwent pyroptosis. NETs were directly engulfed by macrophages and then stimulated AIM2 inflammasome-dependent macrophage pyroptosis in vitro, which amplified the activation of hepatic stellate cells (HSCs) and increased collagen deposition. Administration of the NETs degradation agent DNase I or the AIM2 inflammasome activation inhibitor ODN A151 effectively alleviated chronic liver inflammation/fibrosis progression in vivo.
CONCLUSIONS: NETs-induced AIM2 inflammasome-dependent pyroptosis in macrophages facilitates liver inflammation/fibrosis progression. The identified NET-AIM2 inflammasome cascade could serve as a novel therapeutic target for hepatic inflammation/fibrosis progression.

Keywords:  AIM2 inflammasome; Chronic liver inflammation/fibrosis; Neutrophil extracellular traps; Pyroptosis

DOI:  https://doi.org/10.1186/s12964-024-01944-9
Immunity. 2024 Nov 15. pii: S1074-7613(24)00492-8. [Epub ahead of print]

Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation.

Benedikt S Saller, Svenja Wöhrle, Larissa Fischer, Clara Dufossez, Isabella L Ingerl, Susanne Kessler, Maria Mateo-Tortola, Oliver Gorka, Felix Lange, Yurong Cheng, Emilia Neuwirt, Adinarayana Marada, Christoph Koentges, Chiara Urban, Philipp Aktories, Peter Reuther, Sebastian Giese, Susanne Kirschnek, Carolin Mayer, Johannes Pilic, Hugo Falquez-Medina, Aline Oelgeklaus, Veerasikku Gopal Deepagan, Farzaneh Shojaee, Julia A Zimmermann, Damian Weber, Yi-Heng Tai, Anna Crois, Kevin Ciminski, Remi Peyronnet, Katharina S Brandenburg, Gang Wu, Ralf Baumeister, Thomas Heimbucher, Marta Rizzi, Dietmar Riedel, Martin Helmstädter, Joerg Buescher, Konstantin Neumann, Thomas Misgeld, Martin Kerschensteiner, Peter Walentek, Clemens Kreutz, Ulrich Maurer, Angelika S Rambold, James E Vince, Frank Edlich, Roland Malli, Georg Häcker, Katrin Kierdorf, Chris Meisinger, Anna Köttgen, Stefan Jakobs, Alexander N R Weber, Martin Schwemmle, Christina J Groß, Olaf Groß.

  How mitochondria reconcile roles in functionally divergent cell death pathways of apoptosis and NLRP3 inflammasome-mediated pyroptosis remains elusive, as is their precise role in NLRP3 activation and the evolutionarily conserved physiological function of NLRP3. Here, we have shown that when cells were challenged simultaneously, apoptosis was inhibited and NLRP3 activation prevailed. Apoptosis inhibition by structurally diverse NLRP3 activators, including nigericin, imiquimod, extracellular ATP, particles, and viruses, was not a consequence of inflammasome activation but rather of their effects on mitochondria. NLRP3 activators turned out as oxidative phosphorylation (OXPHOS) inhibitors, which we found to disrupt mitochondrial cristae architecture, leading to trapping of cytochrome c. Although this effect was alone not sufficient for NLRP3 activation, OXPHOS inhibitors became triggers of NLRP3 when combined with resiquimod or Yoda-1, suggesting that NLRP3 activation requires two simultaneous cellular signals, one of mitochondrial origin. Therefore, OXPHOS and apoptosis inhibition by NLRP3 activators provide stringency in cell death decisions.

Keywords:  ATP; NLRP3; OXPHOS; apoptosis; bioenergetics; cell death; chemical biology; cytochrome c; inflammasome; mitochondria; pyroptosis

DOI:  https://doi.org/10.1016/j.immuni.2024.10.012
Immunity. 2024 Nov 14. pii: S1074-7613(24)00490-4. [Epub ahead of print]

A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control.

Yutao Wang, Yanbo Zhang, Kyungsub Kim, Jichang Han, Daniel Okin, Zhaozhao Jiang, Liang Yang, Arum Subramaniam, Terry K Means, Frank O Nestlé, Katherine A Fitzgerald, Gwendalyn J Randolph, Cammie F Lesser, Jonathan C Kagan, Diane Mathis, Christophe Benoist.

Ligand-dependent transcription factors of the nuclear receptor (NR) family regulate diverse aspects of metazoan biology, enabling communications between distant organs via small lipophilic molecules. Here, we examined the impact of each of 35 NRs on differentiation and homeostatic maintenance of all major immunological cell types in vivo through a "Rainbow-CRISPR" screen. Receptors for retinoic acid exerted the most frequent cell-specific roles. NR requirements varied for resident macrophages of different tissues. Deletion of either Rxra or Rarg reduced frequencies of GATA6+ large peritoneal macrophages (LPMs). Retinoid X receptor alpha (RXRα) functioned conventionally by orchestrating LPM differentiation through chromatin and transcriptional regulation, whereas retinoic acid receptor gamma (RARγ) controlled LPM survival by regulating pyroptosis via association with the inflammasome adaptor ASC. RARγ antagonists activated caspases, and RARγ agonists inhibited cell death induced by several inflammasome activators. Our findings provide a broad view of NR function in the immune system and reveal a noncanonical role for a retinoid receptor in modulating inflammasome pathways.

DOI: https://doi.org/10.1016/j.immuni.2024.10.010
Cell Mol Immunol. 2024 Nov 22.

Gasdermin D unlocks metabolic pathways to enhance tissue regeneration.

Quazi T H Shubhra.

DOI: https://doi.org/10.1038/s41423-024-01239-6