bims-inflin Biomed News
on Inflammasome and infection
Issue of 2024–04–21
six papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto
  1. Modulation and Determination of the Status of Inflammasomes in Leishmania-Infected Macrophages.
  2. Flagellin-modulated inflammasome pathways characterize the human alveolar macrophage response to Burkholderia pseudomallei, a lung-tropic pathogen.
  3. Adipose tissue IL-18 production is independent of caspase-1 and caspase-11.
  4. Strategies of bacterial detection by inflammasomes.
  5. Molecular Regulation of NLRP3 Inflammasome Activation During Parasitic Infection.
  6. REV-ERBα negatively regulates NLRP6 transcription and reduces the severity of Salmonella infection in mice.
  1. Methods Mol Biol. 2024 ;2782 137-146
    Modulation and Determination of the Status of Inflammasomes in Leishmania-Infected Macrophages.
    Arunima Biswas, Anindita Bhattacharjee, Pijush K Das.
      Leishmania, an intra-macrophage kinetoplastid parasite, modulates a vast array of defensive mechanisms of the host macrophages to create a comfortable environment for their survival. When the host encounters intracellular pathogens, a multimeric protein complex called NLRP3 inflammasome gets turned on, leading to caspase-1 activation-mediated maturation of IL-1β from its pro-form. However, Leishmania often manages to neutralize inflammasome activation by manipulating negative regulatory molecules of the host itself. Exhaustion of NLRP3 and pro-IL-1β result from decreased NF-κB activity in infection, which was attributed to increased expression of A20, a negative regulator of NF-κB signalling. Moreover, reactive oxygen species, another key requirement for inflammasome activation, are inhibited by mitochondrial uncoupling protein 2 (UCP2) which is upregulated by Leishmania. Inflammasome activation is a complex event and procedures involved in monitoring inflammasome activation need to be accurate and error-free. In this chapter, we summarize the protocol that includes various experimental procedures required for the determination of the status of inflammasomes in Leishmania-infected macrophages.
    Keywords:  Caspase-1; ELISA; IL-1β; Immunoblot; Inflammasomes; Leishmania; Macrophage; NLRP3
    DOI:  https://doi.org/10.1007/978-1-0716-3754-8_10
  2. Infect Immun. 2024 Apr 15. e0006024
    Flagellin-modulated inflammasome pathways characterize the human alveolar macrophage response to Burkholderia pseudomallei, a lung-tropic pathogen.
    Lara Lovelace-Macon, Sarah M Baker, Deirdre Ducken, Sudeshna Seal, Guilhem Rerolle, Diane Tomita, Kelly D Smith, Sandra Schwarz, T Eoin West.
      Melioidosis is an emerging tropical infection caused by inhalation, inoculation, or ingestion of the flagellated, facultatively intracellular pathogen Burkholderia pseudomallei. The melioidosis case fatality rate is often high, and pneumonia, the most common presentation, doubles the risk of death. The alveolar macrophage is a sentinel pulmonary host defense cell, but the human alveolar macrophage in B. pseudomallei infection has never been studied. The objective of this study was to investigate the host-pathogen interaction of B. pseudomallei infection with the human alveolar macrophage and to determine the role of flagellin in modulating inflammasome-mediated pathways. We found that B. pseudomallei infects primary human alveolar macrophages but is gradually restricted in the setting of concurrent cell death. Electron microscopy revealed cytosolic bacteria undergoing division, indicating that B. pseudomallei likely escapes the alveolar macrophage phagosome and may replicate in the cytosol, where it triggers immune responses. In paired human blood monocytes, uptake and intracellular restriction of B. pseudomallei are similar to those observed in alveolar macrophages, but cell death is reduced. The alveolar macrophage cytokine response to B. pseudomallei is characterized by marked interleukin (IL)-18 secretion compared to monocytes. Both cytotoxicity and IL-18 secretion in alveolar macrophages are partially flagellin dependent. However, the proportion of IL-18 release that is driven by flagellin is greater in alveolar macrophages than in monocytes. These findings suggest differential flagellin-mediated inflammasome pathway activation in the human alveolar macrophage response to B. pseudomallei infection and expand our understanding of intracellular pathogen recognition by this unique innate immune lung cell.
    Keywords:  Burkholderia pseudomallei; alveolar macrophage; flagella
    DOI:  https://doi.org/10.1128/iai.00060-24
  3. Immun Inflamm Dis. 2024 Apr;12(4): e1241
    Adipose tissue IL-18 production is independent of caspase-1 and caspase-11.
    Luis Román-Domínguez, Jonathan Salazar-León, Karla F Meza-Sosa, Leonor Pérez-Martínez, Gustavo Pedraza-Alva.
       BACKGROUND: Inflammation in adipose tissue, resulting from imbalanced caloric intake and energy expenditure, contributes to the metabolic dysregulation observed in obesity. The production of inflammatory cytokines, such as IL-1β and IL-18, plays a key role in this process. While IL-1β promotes insulin resistance and diabetes, IL-18 regulates energy expenditure and food intake. Previous studies have suggested that caspase-1, activated by the Nlrp3 inflammasome in response to lipid excess, mediates IL-1β production, whereas activated by the Nlrp1b inflammasome in response to energy excess, mediates IL-18 production. However, this has not been formally tested.
    METHODS: Wild-type and caspase-1-deficient Balb/c mice, carrying the Nlrp1b1 allele, were fed with regular chow or a high-fat diet for twelve weeks. Food intake and mass gain were recorded weekly. At the end of the twelve weeks, glucose tolerance and insulin resistance were evaluated. Mature IL-18 protein levels and the inflammatory process in the adipose tissue were determined. Fasting lipid and cytokine levels were quantified in the sera of the different experimental groups.
    RESULTS: We found that IL-18 production in adipose tissue is independent of caspase-1 activity, regardless of the metabolic state, while Nlrp3-mediated IL-1β production remains caspase-1 dependent. Additionally, caspase-1 null Balb/c mice did not develop metabolic abnormalities in response to energy excess from the high-fat diet.
    CONCLUSION: Our findings suggest that IL-18 production in the adipose tissue is independent of Nlrp3 inflammasome and caspase-1 activation, regardless of caloric food intake. In contrast, Nlrp3-mediated IL-1β production is caspase-1 dependent. These results provide new insights into the mechanisms underlying cytokine production in the adipose tissue during both homeostatic conditions and metabolic stress, highlighting the distinct roles of caspase-1 and the Nlrp inflammasomes in regulating inflammatory responses.
    Keywords:  adipose tissue; animals; cytokines; diabetes; inflammation; macrophage; molecules
    DOI:  https://doi.org/10.1002/iid3.1241
  4. Cell Chem Biol. 2024 Apr 15. pii: S2451-9456(24)00125-9. [Epub ahead of print]
    Strategies of bacterial detection by inflammasomes.
    Jordan B Jastrab, Jonathan C Kagan.
      Mammalian innate immunity is regulated by pattern-recognition receptors (PRRs) and guard proteins, which use distinct strategies to detect infections. PRRs detect bacterial molecules directly, whereas guards detect host cell manipulations by microbial virulence factors. Despite sensing infection through different mechanisms, both classes of innate immune sensors can activate the inflammasome, an immune complex that can mediate cell death and inflammation. Inflammasome-mediated immune responses are crucial for host defense against many bacterial pathogens and prevent invasion by non-pathogenic organisms. In this review, we discuss the mechanisms by which inflammasomes are stimulated by PRRs and guards during bacterial infection, and the strategies used by virulent bacteria to evade inflammasome-mediated immunity.
    DOI:  https://doi.org/10.1016/j.chembiol.2024.03.009
  5. Biosci Rep. 2024 Apr 16. pii: BSR20231918. [Epub ahead of print]
    Molecular Regulation of NLRP3 Inflammasome Activation During Parasitic Infection.
    Rasha Alonaizan.
      Parasitic diseases are a serious global health concern, causing many common and severe infections, including Chagas disease, leishmaniasis,and schistosomiasis. The NLRP3 inflammasome belongs to the NLR (nucleotide-binding domain leucine-rich-repeat-containing proteins) family, which are cytosolic proteins playing key roles in the detection of pathogens. NLRP3 inflammasomes are activated in immune responses to Plasmodium,Leishmania, Toxoplasma gondii, Entamoeba histolytica,Trypanosoma cruzi and other parasites. The role of NLRP3 is not fully understood, but it is a crucial component of the innate immune response to parasitic infections and its functions as a sensor triggering the inflammatory response to the invasive parasites. However, while this response can limit the parasites' growth, it can also result in potentially catastrophic host pathology. This makes it essential to understand how NLRP3 interacts with parasites to initiate the inflammatory response. Plasmodium hemozoin, Leishmania glycoconjugate lipophosphoglycan (LPG) and E. histolytica Gal/GalNAc lectin can stimulate NLRP3 activation, while the dense granule protein 9 (GRA9) of T. gondii has been shown to suppress it. Several other parasitic products also have diverse effects on NLRP3 activation. Understanding the mechanism of NLRP3 interaction with these products will help to develop advanced therapeutic approaches to treat parasitic diseases. This review summarizes current knowledge of the NLRP3 inflammasome's action on the immune response to parasitic infections and aims to determine the mechanisms through which parasitic molecules either activate or inhibit its action.
    Keywords:  Helminths; NLRP3 Inflammasomes; Plasmodium; T. gondii; Trypanosome cruzi
    DOI:  https://doi.org/10.1042/BSR20231918
  6. Heliyon. 2024 Apr 30. 10(8): e28432
    REV-ERBα negatively regulates NLRP6 transcription and reduces the severity of Salmonella infection in mice.
    Lanqing Sun, Kai Huang, Qifeng Deng, Yuan Zhu, Yu Cao, Kedi Dong, Sidi Yang, Yuanyuan Li, Shuyan Wu, Rui Huang.
      Non-typhoidal Salmonella infection is among the most frequent foodborne diseases threatening human health worldwide. The host circadian clock orchestrates daily rhythms to adapt to environmental changes, including coordinating immune function in response to potential infections. However, the molecular mechanisms underlying the interplay between the circadian clock and the immune system in modulating infection processes are incompletely understood. Here, we demonstrate that NLRP6, a novel nucleotide-oligomerization domain (NOD)-like receptor (NLR) family member highly expressed in the intestine, is closely associated with the differential day-night response to Salmonella infection. The core clock component REV-ERBα negatively regulates NLRP6 transcription, leading to the rhythmic expression of NLRP6 and the secretion of IL-18 in intestinal epithelial cells, playing a crucial role in mediating the differential day-night response to Salmonella infection. Activating REV-ERBα with agonist SR9009 in wild-type mice attenuated the severity of infection by decreasing the NLRP6 level in intestinal epithelial cells. Our findings provide new insights into the association between the host circadian clock and the immune response to enteric infections by revealing the regulation of Salmonella infection via the inhibitory effect of REV-ERBα on NLRP6 transcription. Targeting REV-ERBα to modulate NLRP6 activation may be a potential therapeutic strategy for bacterial infections.
    Keywords:  Circadian clock; Intestinal epithelial cell; NLRP6; REV-ERBα; Salmonella Typhimurium
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e28432
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