bims-inflin 2024-09-29 papers

bims-inflin

Biomed News

on Inflammasome and infection

Issue of 2024–09–29
ten papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

The role of inflammasomes as central inflammatory hubs in Mycobacterium tuberculosis infection.
Neonatal neutrophils exhibit reduced NLRP3 inflammasome activation.
Pseudorabies Virus UL4 protein promotes the ASC-dependent inflammasome activation and pyroptosis to exacerbate inflammation.
Molecular mechanisms of zymosan-induced inflammasome activation in macrophages.
Pericentriolar material 1 promotes intestinal inflammation in ulcerative colitis by activating NLRP3/gasdermin D-mediated macrophage pyroptosis.
From fat to fire: The lipid-inflammasome connection.
Activation Pathways of Murine Macrophages by Lipophosphoglycan from Strains of Leishmania major (FV1 and LV39).
Lycium barbarum polysaccharides (LBP) suppresses hypoxia/reoxygenation (H/R)-induced rat H9C2 cardiomyocytes pyroptosis via Nrf2/HO-1 signaling pathway.
Leishmania donovani Modulates Macrophage Lipidome During Infection.
Insights into the role of legionella effectors on host metabolic perturbations.

Front Immunol. 2024 ;15 1436676

The role of inflammasomes as central inflammatory hubs in Mycobacterium tuberculosis infection.

Sebastian J Theobald, Tony A Müller, Dinah Lange, Katharina Keck, Jan Rybniker.

  Mycobacterium tuberculosis (Mtb) infection represents a global health problem and is characterized by formation of granuloma with a necrotic center and a systemic inflammatory response. Inflammasomes have a crucial role in the host immune response towards Mtb. These intracellular multi-protein complexes are assembled in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Inflammasome platforms activate caspases, leading to the maturation of the proinflammatory cytokines interleukin (IL)-1 and 18 and the cleavage of gasdermin D (GSDMD), a pore-forming protein responsible for cytokine release and pyroptotic cell death. Recent in vitro and in vivo findings have highlighted the importance of inflammasome signaling and subsequent necrotic cell death in Mtb-infected innate immune cells. However, we are just beginning to understand how inflammasomes contribute to disease or to a protective immune response in tuberculosis (TB). A detailed molecular understanding of inflammasome-associated pathomechanisms may foster the development of novel host-directed therapeutics or vaccines with improved activity. In this mini-review, we discuss the regulatory and molecular aspects of inflammasome activation and the associated immunological consequences for Mtb pathogenesis.

Keywords:  AIM2 inflammasome; Mycobacterium tuberculosis; NLRP3 inflammasome; drug resistance; gasdermin; inflammasome; interleukin-1; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2024.1436676
J Leukoc Biol. 2024 Sep 23. pii: qiae206. [Epub ahead of print]

Neonatal neutrophils exhibit reduced NLRP3 inflammasome activation.

Lou Martha Wackerbarth, Sonja Birke Seifert, Matteo Napoli, Ina Rohwedder, Thomas Vogl, Christoph Scheiermann, Thomas Kolben, Claudia Nussbaum, Monika Pruenster, Roland Immler, Markus Sperandio.

  Newborns are at high risk to develop sepsis. This is linked to innate immune responses at birth which are not completely adapted to postnatal life. Neutrophils are key players of innate immunity and exhibit a marked ontogenetic regulation of their functionality. Here, we studied the NLRP3 inflammasome in neonatal neutrophils and found lower baseline expression of NLRP3, pro-caspase-1 and the K+-channel KV1.3 compared to adult neutrophils. Following stimulation with LPS/Nigericin, ASC oligomerization, caspase-1 activation and IL-1β release were significantly reduced in neonatal compared to adult neutrophils. Similarly, stimulation of neonatal neutrophils with E-selectin led to reduced NLRP3 inflammasome activation accompanied by diminished release of the alarmin S100A8/A9. Taken together, our results strongly indicate diminished NLRP3 inflammasome activation in neonatal neutrophils leading to a significant reduction of released IL-1β and S100A8/A9. These findings identify reduced neutrophil NLRP3 inflammasome activation as critical component contributing to the inherent susceptibility to infections in neonates.

Keywords:  E-selectin; Inflammation; NLRP3 inflammasome; Neonatal neutrophils; S100A8/A9

DOI:  https://doi.org/10.1093/jleuko/qiae206
PLoS Pathog. 2024 Sep;20(9): e1012546

Pseudorabies Virus UL4 protein promotes the ASC-dependent inflammasome activation and pyroptosis to exacerbate inflammation.

Xiaohua Zhang, Guiyuan Chen, Junqing Yin, Lichen Nie, Linghao Li, Qian Du, Dewen Tong, Yong Huang.

Pseudorabies virus (PRV) infection causes systemic inflammatory responses and inflammatory damages in infected animals, which are associated with the activation of inflammasome and pyroptosis in infected tissues. Here, we identified a critical function of PRV non-structural protein UL4 that enhanced ASC-dependent inflammasome activation to promote pyroptosis. Whereas, the deficiency of viral UL4 was able to reduce ASC-dependent inflammasome activation and the occurrences of pyroptosis. Mechanistically, the 132-145 aa of UL4 permitted its translocation from the nucleus to the cytoplasm to interact with cytoplasmic ASC to promote the activation of NLRP3 and AIM2 inflammasome. Further research showed that UL4 promoted the phosphorylation levels of SYK and JNK to enhance the ASC phosphorylation, which led to the increase of ASC oligomerization, thus promoting the activation of NLRP3 and AIM2 inflammasome and enhanced GSDMD-mediated pyroptosis. In vivo experiments further showed that PRV UL4 (132DVAADAAAEAAAAE145) mutated strain (PRV-UL4mut) infection did not lead to a significant decrease in viral titers at 12 h. p. i, but it induced lower levels of IL-1β, IL-18, and GSDMD-NT, which led to an alleviated inflammatory infiltration and pathological damage in the lungs and brains, and a lower death rate compared with wild-type PRV strain infection. Taken together, our findings unravel that UL4 is an important viral regulator to manipulate the inflammasome signaling and pyroptosis of host cells to promote the pathogenicity of PRV, which might be further exploited as a new target for live attenuated vaccines or therapeutic strategies against pseudorabies in the future.

DOI: https://doi.org/10.1371/journal.ppat.1012546
Cell Signal. 2024 Sep 18. pii: S0898-6568(24)00386-3. [Epub ahead of print]124 111418

Molecular mechanisms of zymosan-induced inflammasome activation in macrophages.

Rangel L Silva, Alexandre H Lopes, Amanda Becerra, Miriam M Fonseca, Alexandre Maganin, Andre L L Saraiva, Fernando Q Cunha, Jose C Alves-Filho, Dario S Zamboni, Thiago M Cunha.

  Zymosan is a β-glucan-rich component derived from the cell walls of Saccharomyces cerevisiae extensively used in research for its potent immunomodulatory properties. It can prompt inflammatory responses such as peritonitis and arthritis, and is particularly used to study the immune response to fungal particles. Although the zymosan induced-release of the proinflammatory cytokine IL-1β by macrophages is an essential mechanism for combating fungal infection and inducing inflammation, the exact processes leading to its release remain not well understood. In this study, we uncover the intracellular mechanisms involved in zymosan induced-release of active IL-1β by peritoneal macrophages. Zymosan initiates pro-IL-1β formation through TLR2/MyD88 activation; however, Dectin-1 activation only amplify the conversion of pro-IL-1β into its active form. The conversion of inactive to active IL-1β upon zymosan stimulation depends on the NLRP3, ASC, and caspase-1 driven by the decrease in intracellular potassium ions. Notably, zymosan-induced activation of caspase-1 does not require phagocytosis. Instead, zymosan induces a rapid drop in the intracellular ATP concentration, which occurs concomitant with caspase-1 and IL-1β activation. Accordingly, disruption of glycolytic flux during zymosan stimulation promotes an additional reduction of intracellular ATP and concurrently amplifies the activation of caspase-1 and IL-1β. These results reveal that fungal recognition by macrophages results in a metabolic dysfunction, leading to a decrease of intracellular ATP associated with inflammasome activation.

Keywords:  ATP; IL-1β; Inflammasome; Macrophages; NLRP3; Zymosan

DOI:  https://doi.org/10.1016/j.cellsig.2024.111418
FASEB J. 2024 Sep 30. 38(18): e70054

Pericentriolar material 1 promotes intestinal inflammation in ulcerative colitis by activating NLRP3/gasdermin D-mediated macrophage pyroptosis.

Junkun Niu, Yunling Wen, Fengrui Zhang, Shijie Li, Jiarong Miao, Hao Liang, Xinyu Bai, Zhong Zeng, Xiaolong Guo, Yinglei Miao.

  Excessive proinflammatory cytokine release induced by pyroptosis plays a vital role in intestinal mucosal inflammation in ulcerative colitis (UC). Several pyroptosis-related factors are regulated by the centrosome. Pericentriolar material 1 (PCM1) is a primary component of centriolar satellites that is present as cytoplasmic granules around the centrosome. Our previous study revealed that PCM1 was highly expressed in UC patients, but the role of PCM1 in UC remains unknown. This study aimed to elucidate the role of PCM1 in the development of UC, especially the mechanism in pyroptosis process of UC. Clinical mucosal sample and dextran sulfate sodium (DSS)-induced colitis mouse were used to reveal the association between PCM1 and intestinal inflammation. Intestinal epithelial cell-specific PCM1-knockout mice were constructed to determine the role of PCM1 in colitis. Finally, PCM1 RNA interference and overexpression assays in THP1 cells were employed to study the molecular mechanisms of PCM1 in inflammatory responses and pyroptosis. We found that PCM1 expression was upregulated in the colonic mucosa of UC patients and positively correlated with inflammatory indicators. PCM1 expression was elevated in DSS-induced colitis mice and was reduced after methylprednisolone treatment. In the DSS colitis model, intestinal-specific PCM1-knockout mice exhibited milder intestinal inflammation and lower pyroptosis levels than wild-type mice. In cell level, PCM1 exerted a proinflammatory effect by activating the NLRP3 inflammasome and triggering subsequent gasdermin D-mediated pyroptosis to release IL-1β and IL-18. In conclusion, PCM1 mediates activation of the NLRP3 inflammasome and gasdermin D-dependent pyroptosis, ultimately accelerating intestinal inflammation in UC. These findings revealed a previously unknown role of PCM1 in initiating intestinal mucosal inflammation and pyroptosis in UC, and this factor is expected to be a regulator in the complex inflammatory network of UC.

Keywords:  intestinal inflammation; pathogenesis; pericentriolar material 1; pyroptosis; ulcerative colitis

DOI:  https://doi.org/10.1096/fj.202401185R
Immunol Rev. 2024 Sep 27.

From fat to fire: The lipid-inflammasome connection.

Paras K Anand.

  Inflammasomes are multiprotein complexes that play a crucial role in regulating immune responses by governing the activation of Caspase-1, the secretion of pro-inflammatory cytokines, and the induction of inflammatory cell death, pyroptosis. The inflammasomes are pivotal in effective host defense against a range of pathogens. Yet, overt activation of inflammasome signaling can be detrimental. The most well-studied NLRP3 inflammasome has the ability to detect a variety of stimuli including pathogen-associated molecular patterns, environmental irritants, and endogenous stimuli released from dying cells. Additionally, NLRP3 acts as a key sensor of cellular homeostasis and can be activated by disturbances in diverse metabolic pathways. Consequently, NLRP3 is considered a key player linking metabolic dysregulation to numerous inflammatory disorders such as gout, diabetes, and atherosclerosis. Recently, compelling studies have highlighted a connection between lipids and the regulation of NLRP3 inflammasome. Lipids are integral to cellular processes that serve not only in maintaining the structural integrity and subcellular compartmentalization, but also in contributing to physiological equilibrium. Certain lipid species are known to define NLRP3 subcellular localization, therefore directly influencing the site of inflammasome assembly and activation. For instance, phosphatidylinositol 4-phosphate plays a crucial role in NLRP3 localization to the trans Golgi network. Moreover, new evidence has demonstrated the roles of lipid biosynthesis and trafficking in activation of the NLRP3 inflammasome. This review summarizes and discusses these emerging and varied roles of lipid metabolism in inflammasome activation. A deeper understanding of lipid-inflammasome interactions may open new avenues for therapeutic interventions to prevent or treat chronic inflammatory and autoimmune conditions.

Keywords:  FASN; NLRP3; cholesterol; cholesterol trafficking; fatty acid biosynthesis; inflammasomes; lipid metabolism; lipids; phosphatidylinositol

DOI:  https://doi.org/10.1111/imr.13403
ACS Infect Dis. 2024 Sep 23.

Activation Pathways of Murine Macrophages by Lipophosphoglycan from Strains of Leishmania major (FV1 and LV39).

Vanessa Mançur Santos, Astrid Madeleine Calero Goicochea, Antônio José Soares Neto, Flávio Henrique Jesus Santos, Jéssica Lobo da Silva, Théo Araújo-Santos, Leonardo Paiva Farias, Claudia Ida Brodskyn, Valéria M Borges, Rodrigo Pedro Soares, Jonilson Berlink Lima.

  Lipophosphoglycan (LPG) is an important Leishmania virulence factor. It is the most abundant surface glycoconjugate in promastigotes, playing an important role in the interaction with phagocytic cells. While LPG is known to modulate the macrophage immune response during infection, the activation mechanisms triggered by this glycoconjugate have not been fully elucidated. This work investigated the role that LPGs purified from two strains of Leishmania major (FV1 and LV39) play in macrophage activation, considering the differences in their biochemical structures. Bone marrow-derived macrophages from BALB/c mice were stimulated with 10 μg/mL purified LPG from the LV39 and FV1 strains. We then measured the production of nitric oxide (NO) and cytokines, the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and the activation of MAPK pathways. LPG from the LV39 strain, which has longer poly-galactosylated side chains, induced a more pro-inflammatory profile than that from the FV1 strain. This included higher production of NO, TNF-α, and PGE2, and increased expression of COX-2 and iNOS. Additionally, the phosphorylation of ERK-1/2 and JNK was elevated in macrophages exposed to LPG from the LV39 strain. No difference in IL-10 production was observed in cells stimulated by both LPG. Thus, intraspecific structural differences in LPG contribute to distinct innate immune responses in macrophages.

Keywords:  Leishmania major; Lipophosphoglycan; cytokines; inflammatory mediators; leishmaniasis; macrophage

DOI:  https://doi.org/10.1021/acsinfecdis.4c00295
Int J Biol Macromol. 2024 Sep 23. pii: S0141-8130(24)06733-3. [Epub ahead of print] 135924

Lycium barbarum polysaccharides (LBP) suppresses hypoxia/reoxygenation (H/R)-induced rat H9C2 cardiomyocytes pyroptosis via Nrf2/HO-1 signaling pathway.

Yi Gao, Huangen Li, Yongkang Que, Weiwen Chen, Shi-Ying Huang, Wenjie Liu, Xiaotong Ye.

  This study aimed to explore the mechanism that Lycium barbarum polysaccharides (LBP) suppress hypoxia/reoxygenation (H/R)-caused pyroptosis in cardiomyocytes (H9C2) via the Nrf2/HO-1 pathway. Initially, we established the cell model of H/R (6 h hypoxia plus with 24 h reoxygenation), and found that 90 μg/mL LBP was the optimal concentration. Subsequently, we confirmed that LBP reduced the pyroptosis rate of cells after H/R, the activity of LDH, the inflammatory factors IL-1β and IL-18, and the levels of pyroptosis-specific markers ASC, NLRP3, and Caspase-1 (mRNAs and proteins). It increased the cell survival rate and the mRNA levels of the Nrf2/HO-1 pathway markers Nrf2 and HO-1, and allowed cytoplasmic Nrf2 protein to enter the nucleus to activate HO-1 protein. The Nrf2 siRNA2 caused the following events in H/R model: (1) the increases of the apoptosis rate, LDH activity, the levels of inflammatory factors (IL-1β and IL-18), the levels of ACS, NLRP3, and Caspase-1 (mRNAs and proteins); and (2) the decreases of the cell survival rate, the mRNA levels of Nrf2 and HO-1, and the protein levels of cytoplasm-Nrf2, nucleus-Nrf2, and HO-1. Therefore we concluded that 90 μg/mL LBP suppressed H/R-induced H9C2 cardiomyocyte pyroptosis via the Nrf2/HO-1 pathway.

Keywords:  H9C2 cardiomyocytes; Hypoxia/Reoxygenation (H/R); Lycium barbarum polysaccharides; Nrf2/HO-1; Pyroptosis

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135924
Parasite Immunol. 2024 Aug-Sep;46(8-9):46(8-9): e13066

Leishmania donovani Modulates Macrophage Lipidome During Infection.

Shams Tabrez, Zeeshan Fatima, Sajjadul Kadir Akand, Areeba Rahman, Saif Hameed, Mohammed Saleem, Yusuf Akhter, Subhash Kumar Yadav, Mohammad Z Ahmed, Yashwant Kumar, Surajit Bhattacharjee, Abdur Rub.

  Obligate intracellular protozoan parasite, Leishmania donovani, causative agent of visceral leishmaniasis, led to impaired macrophage functions. It is well documented that many of these changes were induced by parasite-mediated reduction in macrophage cholesterol content. Leishmania-mediated alteration in the other lipids has not been explored in detail yet. Here, we found that the expression of key cholesterol biosynthetic genes and total cellular cholesterol were reduced during L. donovani infection. Further, we have also identified that this reduction in the cholesterol led to increased membrane fluidity and inhibition of antigen-presenting potential of macrophages. In addition to this, we studied the relative changes in different lipids in THP-1-derived macrophages during L. donovani infection through liquid chromatography-mass spectrometry. We found that Sphingomyelin (16:0) and ceramide (20:1, 26:0 and 26:1) were significantly reduced in infected macrophages. We further observed that the majority of different sub-classes of phospholipids were downregulated significantly. Overall ratio of phosphatidylcholine versus phosphotidylethanolamine was decreased which indicated the compensatory mechanism of cell in response to cholesterol reduction. The observed Leishmania-mediated alteration in macrophage-lipidome provided the novel insights into mechanism of host-pathogen interactions.

Keywords:  ceramide; cholesterol; leishmaniasis; lipids; sphingomyelin

DOI:  https://doi.org/10.1111/pim.13066
Front Cell Infect Microbiol. 2024 ;14 1458276

Insights into the role of legionella effectors on host metabolic perturbations.

Zhihao Wang, Lei Song, Jingai Che, Chunxiuli Li.

  Legionella infection, the causative agent of Legionnaires' disease, represents a significant threat to human health. The pathogenesis of this infection is intricately linked to the complex interactions between the bacterium and its host, resulting in profound metabolic perturbations. Central to these metabolic shifts is the bacterium's modulation of lipid metabolism, with changes in lipid synthesis and breakdown modifying membrane composition and function. These alterations can influence cellular signaling and immune responses, further contributing to disease progression. It also disrupts glucose utilization and lipid metabolism, altering cellular energy production and immune responses. Additionally, Legionella infection perturbs amino acid and protein metabolism, affecting protein synthesis and degradation, leading to changes in cellular functions and immune responses. This mini-review underscores the complexity of metabolic perturbations in Legionella infection and their significance in host-pathogen interactions. Understanding these metabolic shifts provides valuable insights into the pathogenesis of Legionnaires' disease and could lead to the development of novel therapeutic strategies.

Keywords:  glucose; phosphoinositide; protein synthesis; type IV secretion system; virulence

DOI:  https://doi.org/10.3389/fcimb.2024.1458276