Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense

Cell death is an essential immunological apparatus of host defense, but dysregulation of mutually inclusive cell deaths poses severe threats during microbial and parasitic infections leading to deleterious consequences in the pathological progression of infectious diseases. Nucleotide-binding oligomerization domain (NOD)-Leucine-rich repeats (LRR)-containing receptors (NLRs), also called nucleotide-binding oligomerization (NOD)-like receptors (NLRs), are major cytosolic pattern recognition receptors (PRRs), their involvement in the orchestration of innate immunity and host defense against bacteria, viruses, fungi and parasites, often results in the cleavage of gasdermin and the release of IL-1β and IL-18, should be tightly regulated. NLRs are functionally diverse and tissue-specific PRRs expressed by both immune and non-immune cells. Beyond the inflammasome activation, NLRs are also involved in NF-κB and MAPK activation signaling, the regulation of type I IFN (IFN-I) production and the inflammatory cell death during microbial infections. Recent advancements of NLRs biology revealed its possible interplay with pyroptotic cell death and inflammatory mediators, such as caspase 1, caspase 11, IFN-I and GSDMD. This review provides the most updated information that caspase 8 skews the NLRP3 inflammasome activation in PANoptosis during pathogen infection. We also update multidimensional roles of NLRP12 in regulating innate immunity in a content-dependent manner: novel interference of NLRP12 on TLRs and NOD derived-signaling cascade, and the recently unveiled regulatory property of NLRP12 in production of type I IFN. Future prospects of exploring NLRs in controlling cell death during parasitic and microbial infection were highlighted.

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Faculty Opinions recommendation of Converging roles of caspases in inflammasome activation, cell death and innate immunity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726010689.793545006 ◽

2018 ◽

Author(s):

Jerrold Weiss

Keyword(s):

Innate Immunity ◽

Cell Death ◽

Inflammasome Activation

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Thromboinflammation as a Driver of Venous Thromboembolism

Hämostaseologie ◽

10.1055/a-1661-0257 ◽

2021 ◽

Vol 41 (06) ◽

pp. 428-432

Author(s):

Nadine Gauchel ◽

Krystin Krauel ◽

Muataz Ali Hamad ◽

Christoph Bode ◽

Daniel Duerschmied

Keyword(s):

Innate Immunity ◽

Venous Thromboembolism ◽

Host Defense ◽

Thrombus Formation ◽

Pathological Process ◽

Defense Systems ◽

Underlying Mechanisms

AbstractThrombus formation has been identified as an integral part in innate immunity, termed immunothrombosis. Activation of host defense systems is known to result in a procoagulant environment. In this system, cellular players as well as soluble mediators interact with each other and their dysregulation can lead to the pathological process of thromboinflammation. These mechanisms have been under intensified investigation during the COVID-19 pandemic. In this review, we focus on the underlying mechanisms leading to thromboinflammation as one trigger of venous thromboembolism.

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Regiospecific Methylation of a Dietary Flavonoid Scaffold Selectively Enhances IL-1β Production following Toll-like Receptor 2 Stimulation in THP-1 Monocytes

Journal of Biological Chemistry ◽

10.1074/jbc.m113.453514 ◽

2013 ◽

Vol 288 (29) ◽

pp. 21126-21135 ◽

Cited By ~ 11

Author(s):

Eng-Kiat Lim ◽

Paul J. Mitchell ◽

Najmeeyah Brown ◽

Rebecca A. Drummond ◽

Gordon D. Brown ◽

...

Keyword(s):

Innate Immunity ◽

Natural Products ◽

Intestinal Microflora ◽

Rank Order ◽

Inflammasome Activation ◽

Toll Like Receptor ◽

Immune Health ◽

Toll Like Receptor 2 ◽

Dietary Flavonoid ◽

The Impact

It is now recognized that innate immunity to intestinal microflora plays a significant role in mediating immune health, and modulation of microbial sensing may underpin the impact of plant natural products in the diet or when used as nutraceuticals. In this context, we have examined five classes of plant-derived flavonoids (flavonols, flavones, flavanones, catechins, and cyanidin) for their ability to regulate cytokine release induced by the Toll-like receptor 2 (TLR2) agonist Pam3CSK4. We found that the flavonols selectively co-stimulated IL-1β secretion but had no impact on the secretion of IL-6. Importantly, this costimulation of TLR2-induced cytokine secretion was dependent on regiospecific methylation of the flavonol scaffold with a rank order of quercetin-3,4′-dimethylether > quercetin-3-methylether > casticin. The mechanism underpinning this costimulation did not involve enhanced inflammasome activation. In contrast, the methylated flavonols enhanced IL-1β gene expression through transcriptional regulation, involving mechanisms that operate downstream of the initial NF-κB and STAT1 activation events. These studies demonstrate an exquisite level of control of scaffold bioactivity by regiospecific methylation, with important implications for understanding how natural products affect innate immunity and for their development as novel immunomodulators for clinical use.

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Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4

Scientific Reports ◽

10.1038/srep31936 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 13

Author(s):

Zhijuan Qiu ◽

Jorge L. Cervantes ◽

Basak B. Cicek ◽

Subhajit Mukherjee ◽

Madhukumar Venkatesh ◽

...

Keyword(s):

Innate Immunity ◽

Bacterial Infection ◽

Host Defense ◽

Negative Impact ◽

Pregnane X Receptor ◽

Negative Regulator ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Chemokine Production ◽

Inflammatory Monocytes

Abstract The nuclear pregnane X receptor (PXR) plays a central role in regulating xenobiotic metabolism. We now report a novel role for PXR as a critical negative regulator of innate immunity after infection. Pxr −/− mice exhibited remarkably elevated pro-inflammatory cytokine and chemokine production following infection with Listeria monocytogenes (Lm). Despite the more robust innate immune response, Pxr −/− mice were highly susceptible to Lm infection. Surprisingly, disruption of the Toll-like receptor 4 (TLR4) but not TLR2 signaling restored the inflammation to normal levels and the ability to clear Lm in Pxr −/− mice. Mechanistically, the heightened inflammation in Pxr −/− mice resulted in the death of inflammatory monocytes that led to the enhanced susceptibility to Lm infection. These data demonstrated that PXR regulated pathogen-induced inflammation and host defense against Lm infection through modulating the TLR4 pathway. In summary, we discovered an apical role for PXR in regulating innate immunity. In addition, we uncovered a remarkable negative impact of the TLR4 pathway in controlling the quality of the inflammatory response and host defense against a gram-positive bacterial infection.

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Abstract 15894: Adaptations of Innate Immunity in Hibernation: Mechanisms for Protection Against Acute Organ Injury

Circulation ◽

10.1161/circ.132.suppl_3.15894 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Quintin J Quinones ◽

Qing Ma ◽

Michael P Smith ◽

Janet Staats ◽

Cliburn Chan ◽

...

Keyword(s):

Innate Immunity ◽

Cytokine Production ◽

Troponin I ◽

Ischemia Reperfusion ◽

Organ Injury ◽

Inflammasome Activation ◽

Proteomic Profiling ◽

Blood Monocytes ◽

Organ Protection ◽

Altered Expression

Introduction: Hibernation is a natural molecular adaptation to extreme environmental conditions with important implications for perioperative organ protection. Hypothesis: We hypothesized that the hibernator cardioprotective phenotype is accompanied by altered expression of innate immune pattern-recognition receptors (PRRs) and inflammatory pathways. Methods: LV myocardium, peripheral blood monocytes (PBMC), and plasma were collected from rat, summer AGS, and winter AGS after sham, 3h or 24h ischemia/reperfusion (I/R). Results: Plasma troponin I detection confirmed greater I/R injury in rat compared to AGS (Fig 1). Proteomic profiling of LV myocardium detected multiple differences including higher expression of MyD88 dependent toll-like receptors (TLR) in rat compared to AGS; average levels of TLRs were 1.8 fold higher in rat compared with hibernating AGS. Comparison of PBMCs from rat, summer, and hibernating AGS revealed increased PRR expression and cytokine production in the rat compared to the AGS, along the TLR3/TICAM (Fig2), TLR/MyD88, and AIM2/inflammasome axes. Conclusions: Compared to AGS, rats experience robust inflammasome activation in response to I/R as evidenced by >30-fold increases in AIM2 and Caspase 1. Hibernation state differences in innate immunity exist, including reduced expression of PRRs(TLR1,3, and AIM2); additionally signaling via TLR 3 and 4 is greatly dampened in winter AGS due to nearly absent expression of TICAM1. Circulating immune effector cells in winter AGS have an abrogated response to DAMPs compared to cells from summer AGS or rat, as evidenced by reduced cytokine production.

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Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease

Journal of Experimental Medicine ◽

10.1084/jem.20182031 ◽

2019 ◽

Vol 216 (3) ◽

pp. 482-500 ◽

Cited By ~ 29

Author(s):

Kyle Tretina ◽

Eui-Soon Park ◽

Agnieszka Maminska ◽

John D. MacMicking

Keyword(s):

Innate Immunity ◽

Bacterial Infection ◽

Host Defense ◽

Tissue Damage ◽

Binding Proteins ◽

Wide Spectrum ◽

Cell Types ◽

Microbial Pathogens ◽

Health And Disease ◽

Basic Biology

Guanylate-binding proteins (GBPs) have recently emerged as central orchestrators of immunity to infection, inflammation, and neoplastic diseases. Within numerous host cell types, these IFN-induced GTPases assemble into large nanomachines that execute distinct host defense activities against a wide variety of microbial pathogens. In addition, GBPs customize inflammasome responses to bacterial infection and sepsis, where they act as critical rheostats to amplify innate immunity and regulate tissue damage. Similar functions are becoming evident for metabolic inflammatory syndromes and cancer, further underscoring the importance of GBPs within infectious as well as altered homeostatic settings. A better understanding of the basic biology of these IFN-induced GTPases could thus benefit clinical approaches to a wide spectrum of important human diseases.

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