bims-inflin 2024-10-06 papers

bims-inflin

Biomed News

on Inflammasome and infection

Issue of 2024‒10‒06
ten papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

Inflammasomes and their role in PANoptosomes.
The role of TREM-1 in septic myocardial pyroptosis and septic cardiomyopathy in vitro and in vivo.
Leishmania major-induced alteration of host cellular and systemic copper homeostasis drives the fate of infection.
MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice.
Molecular mechanisms of emerging inflammasome complexes and their activation and signaling in inflammation and pyroptosis.
Ornithine lipid is a partial TLR4 agonist and NLRP3 activator.
Both host and parasite non-coding RNAs co-ordinate the regulation of macrophage gene expression to reduce pro-inflammatory immune responses and promote tissue repair pathways during infection with fasciola hepatica.
Ubiquitin-independent degradation of Bim blocks macrophage pyroptosis in sepsis-related tissue injury.
Streptococcus mutans outer membrane vesicles affect inflammasome activation and the glycolysis of macrophages.
Oxysterol binding protein regulates the resolution of TLR-induced cytokine production in macrophages.

Curr Opin Immunol. 2024 Sep 27. pii: S0952-7915(24)00079-7. [Epub ahead of print]91 102489

Inflammasomes and their role in PANoptosomes.

Vinod Nadella, Thirumala-Devi Kanneganti.

Inflammasomes are multiprotein signaling structures in the innate immune system that drive cell death and inflammatory responses. These protein complexes generally comprise an innate immune sensor, the adaptor protein ASC, and the inflammatory protease caspase-1. Inflammasomes are formed when a cytosolic sensor, also known as a pattern recognition receptor, senses its cognate ligand, which can include microbial components, endogenous damage/danger signals, or environmental stimuli. Inflammasome assembly leads to autoproteolytic cleavage and activation of caspase-1. This activation, in turn, induces proteolytic maturation and release of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and the activation of the pore-forming molecule gasdermin D to induce cell death, known as pyroptosis. Recent studies have identified inflammasomes as integral components of larger cell death complexes, known as PANoptosomes. These PANoptosomes regulate PANoptosis, an innate immune cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting serine/threonine protein kinases. PANoptosome assembly and activation leads to cell lysis, inflammation, and the release of proinflammatory cytokines, damage-associated molecular patterns, and alarmins. In this review, we discuss the current understanding of different inflammasomes and their role in PANoptosomes.

DOI: https://doi.org/10.1016/j.coi.2024.102489
J Cell Physiol. 2024 Sep 30. e31445

The role of TREM-1 in septic myocardial pyroptosis and septic cardiomyopathy in vitro and in vivo.

Yongxia Chen, Lixia Mao, Songtao Liu, Shunyi Huang, Qiuyun Lin, Man Zeng, Huiyi Huang, Xiaocong Sun, Hongpeng Chen, Jiahao Huang, Gaosheng Zhou, Liehua Deng.

  Septic cardiomyopathy (SCM) is an acute cardiac dysfunction involving myocardial cell pyroptosis. TREM-1 is a known receptor on cell membrane that can amplify the inflammatory response. Our previous studies have shown that TREM-1 in cardiomyocytes is involved in the activation of NLRP3 through the SMC4/NEMO pathway. Here, we aimed to use Trem-1 and Nlrp3 knockout mice to verify the effect of TREM-1 through NLRP3 on cardiac function in septic mice. The results showed that TREM-1 knockout resulted in a decrease in the release of downstream cell signals, including SMC4 and NLRP3, resulting in a decrease in cytokine release and improvement of cardiac dysfunction. Knockout of NLRP3 also reduced cardiomyocyte pyroptosis and increased survival rate. The therapeutic targeting of TREM-1 activation of NLRP3 and its pathway may contribute to the treatment or prevention of SCM.

Keywords:  NLRP3; SMC4; TREM‐1; pyroptosis; septic cardiomyopathy

DOI:  https://doi.org/10.1002/jcp.31445
Commun Biol. 2024 Sep 30. 7(1): 1226

Leishmania major-induced alteration of host cellular and systemic copper homeostasis drives the fate of infection.

Rupam Paul, Adrija Chakrabarty, Suman Samanta, Swastika Dey, Raviranjan Pandey, Saptarshi Maji, Aidan T Pezacki, Christopher J Chang, Rupak Datta, Arnab Gupta.

Copper plays a key role in host-pathogen interaction. We find that during Leishmania major infection, the parasite-harboring macrophage regulates its copper homeostasis pathway in a way to facilitate copper-mediated neutralization of the pathogen. Copper-ATPase ATP7A transports copper to amastigote-harboring phagolysosomes to induce stress on parasites. Leishmania in order to evade the copper stress, utilizes a variety of manipulative measures to lower the host-induced copper stress. It induces deglycosylation and degradation of host-ATP7A and downregulation of copper importer, CTR1 by cysteine oxidation. Additionally, Leishmania induces CTR1 endocytosis that arrests copper uptake. In mouse model of infection, we report an increase in systemic bioavailable copper in infected animals. Heart acts as the major organ for diverting its copper reserves to systemic circulation to fight-off infection by downregulating its CTR1. Our study explores reciprocal mechanism of manipulation of host copper homeostasis pathway by macrophage and Leishmania to gain respective advantages in host-pathogen interaction.

DOI: https://doi.org/10.1038/s42003-024-06716-2
Nat Commun. 2024 Oct 04. 15(1): 8624

MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice.

Kelvin Ka-Lok Wu, Xiaofan Xu, Manyin Wu, Xiaomu Li, Moinul Hoque, Gloria Hoi Yee Li, Qizhou Lian, Kekao Long, Tongxi Zhou, Hailong Piao, Aimin Xu, Hannah Xiaoyan Hui, Kenneth King-Yip Cheng.

M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplodeletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways.

DOI: https://doi.org/10.1038/s41467-024-53006-w
Immunol Rev. 2024 Oct 01.

Molecular mechanisms of emerging inflammasome complexes and their activation and signaling in inflammation and pyroptosis.

Abhimanu Pandey, Zheyi Li, Manjul Gautam, Aritra Ghosh, Si Ming Man.

  Inflammasomes are multi-protein complexes that assemble within the cytoplasm of mammalian cells in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), driving the secretion of the pro-inflammatory cytokines IL-1β and IL-18, and pyroptosis. The best-characterized inflammasome complexes are the NLRP3, NAIP-NLRC4, NLRP1, AIM2, and Pyrin canonical caspase-1-containing inflammasomes, and the caspase-11 non-canonical inflammasome. Newer inflammasome sensor proteins have been identified, including NLRP6, NLRP7, NLRP9, NLRP10, NLRP11, NLRP12, CARD8, and MxA. These inflammasome sensors can sense PAMPs from bacteria, viruses and protozoa, or DAMPs in the form of mitochondrial damage, ROS, stress and heme. The mechanisms of action, physiological relevance, consequences in human diseases, and avenues for therapeutic intervention for these novel inflammasomes are beginning to be realized. Here, we discuss these emerging inflammasome complexes and their putative activation mechanisms, molecular and signaling pathways, and physiological roles in health and disease.

Keywords:  PANoptosis; PANoptosome; autoimmunity; autoinflammation; bacteria; cancer; caspase‐1; caspase‐11; caspase‐4; caspase‐5; cell death; cytokines; gasdermin D; immunity; infection; inflammatory caspases; interferons; lipopolysaccharide; parasites; pattern‐recognition receptors; viruses

DOI:  https://doi.org/10.1111/imr.13406
Cell Rep. 2024 Sep 26. pii: S2211-1247(24)01139-2. [Epub ahead of print]43(10): 114788

Ornithine lipid is a partial TLR4 agonist and NLRP3 activator.

Malvina Pizzuto, Laura Hurtado-Navarro, Cristina Molina-Lopez, Jalal Soubhye, Michel Gelbcke, Silvia Rodriguez-Lopez, Jean-Marie Ruysschaert, Kate Schroder, Pablo Pelegrin.

  Gram-negative bacterial lipopolysaccharides (LPSs) trigger inflammatory reactions through Toll-like receptor 4 (TLR4) and prime myeloid cells for inflammasome activation. In phosphate-limited environments, bacteria reduce LPS and other phospholipid production and synthesize phosphorus-free alternatives such as amino-acid-containing lipids like the ornithine lipid (OL). This adaptive strategy conserves phosphate for other essential cellular processes and enhances bacterial survival in host environments. While OL is implicated in bacterial pathogenicity, the mechanism is unclear. Using primary murine macrophages and human mononuclear cells, we elucidate that OL activates TLR4 and induces potassium efflux-dependent nucleotide-binding domain and leucine-rich repeat-containing pyrin protein 3 (NLRP3) activation. OL upregulates the expression of NLRP3 and pro-interleukin (IL)-1β and induces cytokine secretion in primed and unprimed cells. By contrast, in the presence of LPS, OL functions as a partial TLR4 antagonist and reduces LPS-induced cytokine secretion. We thus suggest that in phosphate-depleted environments, OL replaces LPS bacterial immunogenicity, while constitutively present OL may allow bacteria to escape immune surveillance.

Keywords:  CP: Immunology; CP: Microbiology; IL-1β; NLRP3; TLR; Toll-like receptor; bacteria; caspase; inflammasome; ionizable lipid; lipopolysaccharide; ornithine lipids

DOI:  https://doi.org/10.1016/j.celrep.2024.114788
RNA Biol. 2024 Jan;21(1): 62-77

Both host and parasite non-coding RNAs co-ordinate the regulation of macrophage gene expression to reduce pro-inflammatory immune responses and promote tissue repair pathways during infection with fasciola hepatica.

Dayna Sais, Sumaiya Chowdhury, John P Dalton, Nham Tran, Sheila Donnelly.

  Parasitic worms (helminths) establish chronic infection within mammalian hosts by strategically regulating their host's immune responses. Deciphering the mechanisms by which host non-coding RNAs (ncRNA) co-ordinate the activation and regulation of immune cells is essential to understanding host immunity and immune-related pathology. It is also important to comprehend how pathogens secrete specific ncRNAs to manipulate gene expression of host immune cells and influence their response to infection. To investigate the contribution of both host and helminth derived ncRNAs to the activation and/or regulation of innate immune responses during a parasite infection, we examined ncRNA expression in the peritoneal macrophages from mice infected with Fasciola hepatica. We discovered the presence of several parasitic-derived miRNAs within host macrophages at 6 hrs and 18 hrs post infection. Target prediction analysis showed that these Fasciola miRNAs regulate host genes associated with the activation of host pro-inflammatory macrophages. Concomitantly, there was a distinct shift in host ncRNA expression, which was significant at 5 days post-infection. Prediction analysis suggested that these host ncRNAs target a different cohort of host genes compared to the parasite miRNAs, although the functional outcome was predicted to be similar i.e. reduced pro-inflammatory response and the promotion of a reparative/tolerant phenotype. Taken together, these observations uncover the interplay between host and parasitic ncRNAs and reveal a complementary regulation of the immune response that allows the parasite to evade immune detection and promote tissue repair for the host. These findings will provide a new understanding of the molecular interaction between parasites and host.

Keywords:  Fasciola hepatica; helminth; host-parasite interactions; immune-regulation; lncRNA; macrophages; miRNA; non-coding miRNAs; pro-inflammatory response

DOI:  https://doi.org/10.1080/15476286.2024.2408706
Cell Death Dis. 2024 Sep 30. 15(9): 703

Ubiquitin-independent degradation of Bim blocks macrophage pyroptosis in sepsis-related tissue injury.

Peilin Shi, Yingying Du, Yunyan Zhang, Bo Yang, Qiujing Guan, Yiming Jing, Hao Tang, Jianguo Tang, Chunhui Yang, Xiaoli Ge, Shihui Shen, Lei Li, Chunrong Wu.

Pyroptosis, a typical inflammatory cell death mode, has been increasingly demonstrated to have therapeutic value in inflammatory diseases such as sepsis. However, the mechanisms and therapeutic targets of sepsis remain elusive. Here, we reported that REGγ inhibition promoted pyroptosis by regulating members of the gasdermin family in macrophages. Mechanistically, REGγ directly degraded Bim, a factor of the Bcl-2 family that can inhibit the cleavage of GSDMD/E, ultimately preventing the occurrence of pyroptosis. Furthermore, cecal ligation and puncture (CLP)-induced sepsis model mice showed downregulation of REGγ at both the RNA and protein levels. Gasdermin-mediated pyroptosis was augmented in REGγ-knockout mice, and these mice exhibited more severe sepsis-related tissue injury. More importantly, we found that REGγ expression was downregulated in clinical sepsis samples, such as those from patients with Pseudomonas aeruginosa (PA) infection. Finally, PA-infected mice showed decreased REGγ levels in the lung. In summary, our study reveals that the REGγ-Bim-GSDMD/E pathway is a novel regulatory mechanism of pyroptosis in sepsis-related tissue injury.

DOI: https://doi.org/10.1038/s41419-024-07072-z
Microb Pathog. 2024 Oct 02. pii: S0882-4010(24)00461-3. [Epub ahead of print] 106994

Streptococcus mutans outer membrane vesicles affect inflammasome activation and the glycolysis of macrophages.

Gongyuan Song, Min Li, Bing Zhou, Hongguang Qi, Jie Guo.

  Recent studies indicate that bacterial outer membrane vesicles (OMVs) play a significant role in bacterial virulence and pathogenicity. Streptococcus mutans (S. mutans), a principal pathogen in dental caries, secretes a substantial number of OMVs. However, the impact of S. mutans OMVs on oral health and their underlying pathogenic mechanisms remain poorly understood. Macrophages were the initial innate immune cells to respond to bacterial invaders and their products. Therefore, we purified S. mutans OMVs, which stimulated macrophages. Compared to controls, RT-PCR and ELISA analyses revealed that S. mutans OMVs significantly increased the production of IL-1β, IL-6, TNF-α and IL-8, with IL-1β being notably elevated. IL-1β production and secretion are tightly regulated by the inflammasome. Western blot analyses demonstrated that S. mutans OMVs upregulated the expression of inflammasome components, including NLRP3, NLRC4, ASC and AIM2, with a marked increase in NLRP3 expression. Silencing different inflammasome components with siRNA revealed a reduction in IL-1β secretion induced by S. mutans OMVs, particularly through NLRP3. Additionally, ATP production and K+ efflux were found to be crucial for NLRP3 activation. Prolonged stimulation with S. mutans OMVs resulted in increased lactate production and elevated expression of glycolysis-related genes Glut-1, PFKFB3, and HK I, indicating that S. mutans OMVs significantly induce macrophage glycolysis. Furthermore, S. mutans OMVs were shown to enhance biofilm formation, increase S. mutans colonisation on epithelial cells, and inhibit macrophage phagocytosis, thereby improving the survival of S. mutans in the oral cavity. In summary, S. mutans OMVs promote the survival of S. mutans in the mouth through multiple mechanisms, potentially influencing the development of dental caries.

Keywords:  Oral bacteria; S. mutans OMVs; biofilm; glycolysis; inflammasome; macrophages

DOI:  https://doi.org/10.1016/j.micpath.2024.106994
Proc Natl Acad Sci U S A. 2024 Aug 13. 121(33): e2406492121

Oxysterol binding protein regulates the resolution of TLR-induced cytokine production in macrophages.

Alan H Diercks, Irina S Podolskaia, Tara A Murray, Ana N Jahn, Dat Mai, Dong Liu, Lynn M Amon, Yoshimi Nakagawa, Hitoshi Shimano, Alan Aderem, Elizabeth S Gold.

  Toll-like receptors (TLRs) on macrophages sense microbial components and trigger the production of numerous cytokines and chemokines that mediate the inflammatory response to infection. Although many of the components required for the activation of the TLR pathway have been identified, the mechanisms that appropriately regulate the magnitude and duration of the response and ultimately restore homeostasis are less well understood. Furthermore, a growing body of work indicates that TLR signaling reciprocally interacts with other fundamental cellular processes, including lipid metabolism but only a few specific molecular links between immune signaling and the macrophage lipidome have been studied in detail. Oxysterol-binding protein (Osbp) is the founding member of a family of lipid-binding proteins with diverse functions in lipid sensing, lipid transport, and cell signaling but its role in TLR responses is not well defined. Here, we demonstrate that altering the state of Osbp with its natural ligand, 25-hydroxycholesterol (25HC), or pharmacologically, sustains and thereby amplifies Tlr4-induced cytokine production in vitro and in vivo. CRISPR-induced knockdown of Osbp abrogates the ability of these ligands to sustain TLR responses. Lipidomic analysis suggested that the effect of Osbp on TLR signaling may be mediated by alterations in triglyceride production and treating cells with a Dgat1 inhibitor, which blocks triglyceride production and completely abrogates the effect of Osbp on TLR signaling. Thus, Osbp is a sterol sensor that transduces perturbations of the lipidome to modulate the resolution of macrophage inflammatory responses.

Keywords:  25-hydroxycholesterol; Osbp; immunometabolism; macrophage; toll-like receptor

DOI:  https://doi.org/10.1073/pnas.2406492121