scholarly journals Role of the Inflammasome, IL-1β, and IL-18 in Bacterial Infections

2011 ◽  
Vol 11 ◽  
pp. 2037-2050 ◽  
Author(s):  
Manoranjan Sahoo ◽  
Ivonne Ceballos-Olvera ◽  
Laura del Barrio ◽  
Fabio Re
Keyword(s):  
Bacterial Infections ◽  
Innate Immune ◽  
Host Responses ◽  
Inflammasome Activation ◽  
Different Types ◽  
Molecular Aspects ◽  
Immune Pathway ◽  
Innate Immune Pathway ◽  
Receptor Family

The inflammasome is an important innate immune pathway that regulates at least two host responses protective against infections: (1) secretion of the proinflammatory cytokines IL-1βand IL-18 and (2) induction of pyroptosis, a form of cell death. Inflammasomes, of which different types have been identified, are multiprotein complexes containing pattern recognition receptors belonging to the Nod-like receptor family or the PYHIN family and the protease caspase-1. The molecular aspects involved in the activation of different inflammasomes by various pathogens are being rapidly elucidated, and their role during infections is being characterized. Production of IL-1βand IL-18 and induction of pyroptosis of the infected cell have been shown to be protective against many infectious agents. Here, we review the recent literature concerning inflammasome activation in the context of bacterial infections and identify important questions to be answered in the future.

scholarly journals Targeting macrophage priming by polyphyllin VII triggers anti-tumor immunity via STING-governed cytotoxic T-cell infiltration in lung cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jinglu Yu ◽  
Haibin Deng ◽  
Zhenye Xu
Keyword(s):  
Immune Cells ◽  
Expression Patterns ◽  
Immune Checkpoint Blockade ◽  
Innate Immune ◽  
Cytotoxic T Cell ◽  
T Cell Infiltration ◽  
Immune Pathway ◽  
Innate Immune Pathway ◽  
Pathogenic Infection

AbstractStimulator of interferon genes (STING) controlled innate immune pathway is essential for host defense against pathogenic infection and effective anti-tumor adaptive immunity initiation. Although macrophages transformed across diverse phenotypes play crucial roles in anti-tumor immune response, events determining this transformation and the host-intrinsic role of STING in this process remain controversial. Here we report how STING signaling acts as a key switch to dominate the gene expression patterns of macrophage transformation for promoting priming and releasing immunosuppression. Furthermore, polyphyllin VII, a potential STING agonist, exerts anti-tumor efficacy upon macrophages priming and subsequent cytotoxic T lymphocytes intratumoral infiltration. Meanwhile, the simultaneous PD-L1 amplification on macrophages in response to PP VII is also ruled by STING, thus PP VII may benefit immune-checkpoint blockade therapy for combining. Moreover, PP VII suppresses carcinogenesis upon restraining the immunosuppressed macrophage transformation. This is due to the boosted STING that negatively regulates a STAT3 propagated crosstalk between immune cells and tumor cells. Overall, PP VII-stimulated STING in macrophages provides a paradigm for anti-tumor, and if possible, anti-infection immunotherapy.

scholarly journals Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 83
Author(s):  
Benoit R. Gauthier ◽  
Petra I. Lorenzo ◽  
Valentine Comaills
Keyword(s):  
Nuclear Envelope ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Innate Immune ◽  
Genomic Aberration ◽  
Key Driver ◽  
Immune Pathway ◽  
Sting Pathway ◽  
Innate Immune Pathway

During metastasis, invading tumor cells and circulating tumor cells (CTC) face multiple mechanical challenges during migration through narrow pores and cell squeezing. However, little is known on the importance and consequences of mechanical stress for tumor progression and success in invading a new organ. Recently, several studies have shown that cell constriction can lead to nuclear envelope rupture (NER) during interphase. This loss of proper nuclear compartmentalization has a profound effect on the genome, being a key driver for the genome evolution needed for tumor progression. More than just being a source of genomic alterations, the transient nuclear envelope collapse can also support metastatic growth by several mechanisms involving the innate immune response cGAS/STING pathway. In this review we will describe the importance of the underestimated role of cellular squeezing in the progression of tumorigenesis. We will describe the complexity and difficulty for tumor cells to reach the metastatic site, detail the genomic aberration diversity due to NER, and highlight the importance of the activation of the innate immune pathway on cell survival. Cellular adaptation and nuclear deformation can be the key to the metastasis success in many unsuspected aspects.

scholarly journals The role of innate immune pathway in repeated social defeat stress-induced behavioral changes in mice

2018 ◽  
Vol WCP2018 (0) ◽  
pp. PO3-1-20
Author(s):  
Shiho Kitaoka ◽  
Xiang Nie ◽  
Kohei Tanaka ◽  
Atsubumi Ogawa ◽  
Fumitake Nakano ◽  
...  
Keyword(s):  
Social Defeat ◽  
Innate Immune ◽  
Behavioral Changes ◽  
Social Defeat Stress ◽  
Immune Pathway ◽  
Innate Immune Pathway

scholarly journals Chronic immune response dysregulation in MDS pathogenesis

Blood ◽  
2018 ◽  
Vol 132 (15) ◽  
pp. 1553-1560 ◽  
Author(s):  
Laura Barreyro ◽  
Timothy M. Chlon ◽  
Daniel T. Starczynowski
Keyword(s):  
Immune Response ◽  
Innate Immune ◽  
Direct Role ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Pathway Activation ◽  
Immune Pathway ◽  
Innate Immune Pathway ◽  
Inflammatory Component

Abstract Chronic innate immune signaling in hematopoietic cells is widely described in myelodysplastic syndromes (MDS), and innate immune pathway activation, predominantly via pattern recognition receptors, increases the risk of developing MDS. An inflammatory component to MDS has been reported for many years, but only recently has evidence supported a more direct role of chronic innate immune signaling and associated inflammatory pathways in the pathogenesis of MDS. Here we review recent findings and discuss relevant questions related to chronic immune response dysregulation in MDS.

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis

Gut ◽  
2019 ◽  
Vol 68 (8) ◽  
pp. 1477-1492 ◽  
Author(s):  
Lijun Liao ◽  
Kai Markus Schneider ◽  
Eric J C Galvez ◽  
Mick Frissen ◽  
Hanns-Ulrich Marschall ◽  
...  
Keyword(s):  
Immune Response ◽  
Liver Injury ◽  
Sclerosing Cholangitis ◽  
Functional Role ◽  
Innate Immune ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Intestinal Dysbiosis ◽  
Nlrp3 Inflammasome Activation

ObjectiveThere is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut–liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2−/−) model resembling human primary sclerosing cholangitis (PSC).DesignMale Mdr2−/−, Mdr2−/− crossed with hepatocyte-specific deletion of caspase-8 (Mdr2−/−/Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2−/−-associated intestinal dysbiosis was studied by microbiota transfer experiments.ResultsMdr2−/− mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut–liver axis. Intestinal dysbiosis in Mdr2−/− mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2−/− microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.ConclusionsMDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.

Role of Inflammasome Activation in Systemic Lupus Erythematosus: Are Innate Immune Cells Activated?

2020 ◽  
Author(s):  
Rodolfo Perez-Alamino ◽  
Raquel Cuchacovich ◽  
Luis R. Espinoza ◽  
Constance P. Porretta ◽  
Arnold H. Zea
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Innate Immune Cells ◽  
Systemic Lupus

scholarly journals Brevinin-2 Drug Family—New Applied Peptide Candidates Against Methicillin-Resistant Staphylococcus aureus and Their Effects on Lys-7 Expression of Innate Immune Pathway DAF-2/DAF-16 in Caenorhabditis elegans

2018 ◽  
Vol 8 (12) ◽  
pp. 2627
Author(s):  
Hui Xie ◽  
Yonghua Zhan ◽  
Xueli Chen ◽  
Qi Zeng ◽  
Dan Chen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Survival Rate ◽  
Caenorhabditis Elegans ◽  
Antimicrobial Peptides ◽  
Real Time ◽  
Innate Immune ◽  
C Elegans ◽  
New Drug ◽  
Immune Pathway ◽  
Innate Immune Pathway

The issue of Staphylococcus aureus (MRSA) developing a resistance to drugs such as methicillin has long been the focus for new drug development. In recent years, antimicrobial peptides, such as small molecular peptides with broad-spectrum antibacterial activity and special antibacterial mechanism, have shown a strong medicinal potential. In particular, the Brevinin-2 family has been shown to have a significant inhibitory effect against gram-positive bacteria (G+). In this study, we researched the influence of MRSA on the behavior and survival rate of nematodes. We established an assay of Caenorhabditis elegans–MRSA antimicrobial peptides to screen for new potent anti-infective peptides against MRSA. From the Brevinin-2 family, 13 peptides that had shown strong effects on G+ were screened for their ability to prolong the lifespan of infected worms. Real-time Polymerase Chain Reaction (PCR) tests were used to evaluate the effect on the innate immune pathway dauer formation defective (DAF)-2/DAF-16 of C. elegans. The assay successfully screened and filtered out four of the 13 peptides that significantly improved the survival rate of MRSA-infected worms. The result of real-time PCR indicated that the mRNA and protein expression levels of lys-7 were consistently upregulated by being treated with four of the Brevinin-2 family. The Brevinin-2 family peptides, including Brevinin-2, Brevinin-2-OA3, Brevinin-2ISb, and Brevinin-2TSa, also played an active role in the DAF-2/DAF-16 pathway in C. elegans. We successfully demonstrated the utility of anti-infective peptides that prolong the survival rate of the MRSA-infected host and discovered the relationship between antibacterial peptides and the innate immune system of C. elegans. We demonstrated the antimicrobial effects of Brevinin-2 family peptides, indicating their potential for use as new drug candidates against MRSA infections.

scholarly journals Human Cytomegalovirus UL138 Protein Inhibits the STING Pathway and Reduces Interferon Beta mRNA Accumulation during Lytic and Latent Infections

mBio ◽  
2021 ◽  
Author(s):  
Emily R. Albright ◽  
Clayton K. Mickelson ◽  
Robert F. Kalejta
Keyword(s):  
Innate Immunity ◽  
Interferon Beta ◽  
Viral Latency ◽  
Arms Race ◽  
Innate Immune ◽  
Mrna Accumulation ◽  
Immune Pathway ◽  
Sting Pathway ◽  
Innate Immune Pathway

While a cellular restriction versus viral countermeasure arms race between innate immunity and viral latency is expected, few examples have been documented. Our identification of the first HCMV latency protein that inactivates the cGAS/STING/TBK1 innate immune pathway opens the door to understanding how innate immunity, or its neutralization, impacts long-term persistence by HCMV and other latent viruses.

scholarly journals Updating the NLRC4 Inflammasome: from Bacterial Infections to Autoimmunity and Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiexia Wen ◽  
Bin Xuan ◽  
Yang Liu ◽  
Liwei Wang ◽  
Li He ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Immune Defense ◽  
Innate Immune ◽  
Sensor Protein ◽  
Different Types ◽  
Microbial Infections ◽  
Activation Mechanisms ◽  
Specific Protease

Inflammasomes comprise a family of cytosolic multi-protein complexes that modulate the activation of cysteine-aspartate-specific protease 1 (caspase-1) and promote the maturation and secretion of interleukin (IL)-1β and IL-18, leading to an inflammatory response. Different types of inflammasomes are defined by their sensor protein which recognizes pathogenic ligands and then directs inflammasome assembly. Although the specific molecular mechanisms underlying the activation of most inflammasomes are still unclear, NLRC4 inflammasomes have emerged as multifaceted agents of the innate immune response, playing important roles in immune defense against a variety of pathogens. Other studies have also expanded the scope of NLRC4 inflammasomes to include a range of inherited human autoimmune diseases as well as proposed roles in cancer. In this review article, we provide an updated overview of NLRC4 inflammasomes, describing their composition, activation mechanisms and roles in both microbial infections and other disease conditions.

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