Revisiting Caspase-11 Function in Host Defense

Ng, Tessie M; Monack, Denise M.

doi:10.1016/j.chom.2013.06.009

Cited by 30 publications

(34 citation statements)

References 44 publications

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“…Caspase-11, independently of TLR-4, is also involved in apoptosis induced by LPS (18,19). LPS acts in association with caspase-11, producing an inflammasome following entry to macrophages, and active IL-1 is liberated by the inflammasome under the stimulation of caspase-11 (20,21). In the present study, the level of p-p38 was markedly increased in the LPS group, which was decreased following treatment with MSCs.…”

Section: Discussionsupporting

confidence: 51%

Effects of bone marrow mesenchymal stem cells on the cardiac function and immune system of mice with endotoxemia

Zhou

et al. 2016

Molecular Medicine Reports

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Abstract. The present study aimed to investigate the effects of bone marrow mesenchymal stem cells (MSCs) on the cardiac function and immune system of mice with endotoxemia. The mice were divided into the following groups: Control group, endotoxemia group, lipopolysaccharide (LPS) treatment group, LPS and MSC treatment group (LPS + MSC group) and MSC group. Following treatment with LPS, the cardiac function of the mice was examined at after 2, 6 and 24 h, and on day 7. An enzyme-linked immunofluorescent assay was used to analyze the serum and the levels of cytokines in the myocardium, and western blotting was used to investigate any changes in the levels of signaling proteins associated with the myocardium. A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay was used to investigate the growth rate of the splenic cells at after 24 h and on day 7, and the humoral immune function and phagocytosis of the macrophages in the mice were also examined. The cardiac function of the mice with endotoxemia declined, although this impairment was circumvented following treatment with MSCs. The levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α and IL-10 in the serum and the myocardium increased following stimulation by LPS, although these declined as a result of MSC treatment. The expression levels of Toll-like receptor 4, p65-nuclear factor-κB and phosphorylated p38 in the mouse myocardium were enhanced following stimulation by LPS, which subsequently decreased as a result of MSC treatment. Compared with the control group, the growth rate of the splenic cells, humoral immune function and the level of phagocytosis of macrophages were all increased, although these parameters declined following treatment with MSCs. Taken together, the present study revealed that the MSCs inhibited the inflammatory reaction in the mice with endotoxemia, and improved cardiac function. By contrast, the cellular and humoral immunity were depressed, and phagocytosis of the macrophages, which were enhanced following simulation with LPS, were decreased following treatment with MSCs. However, no overexpression of the anti-inflammatory factor, IL-10, was observed. The present study hypothesized that MSCs exert a bifunctional role in endotoxemia, by inhibiting inflammatory factors, including IL-1 and IL-6, and inhibiting the compensatory expression of IL-10 following LPS stimulation. This avoids the possibility of excessive inhibition of immunological function, as this results in immunosuppression, and a higher ratio of IL-10 to TNF-α is indicative of a poor prognosis in patients with sepsis.

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Section: Discussionsupporting

confidence: 51%

Effects of bone marrow mesenchymal stem cells on the cardiac function and immune system of mice with endotoxemia

Zhou

et al. 2016

Molecular Medicine Reports

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“…Activation of the NLRP3 inflammasome generates active IL-1β or IL-18, central pro-inflammatory mediators that have been linked to atherosclerosis and many other inflammatory diseases, through cleavage of pro-IL1 or pro-IL18 by caspase 1/11 86 . The NLRP3 inflammasome is a sensor for various crystals such as those in gout, as well as cholesterol crystals 85, 87 , and in turn activates caspase-1 or caspase 11 86 . NLRP3 activation cannot generate active IL-1β/IL-18 if its substrates proIL-1β /IL-18 have not been induced.…”

Section: Plaque Progressionmentioning

confidence: 99%

Mechanisms That Regulate Macrophage Burden in Atherosclerosis

Randolph

2014

Circulation Research

230

194

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Mononuclear phagocytes (MPs) relevant to atherosclerosis include monocytes, macrophages, and dendritic cells (DCs). A decade ago, studies on macrophage behavior in atherosclerotic lesions were often limited to quantification of total macrophage area in cross-sections of plaques. While technological advances are still needed to examine plaque MP populations in an increasingly dynamic and informative manner, innovative methods to interrogate the biology of MPs in atherosclerotic plaques developed in the last few years point to a number of mechanisms that regulate the accumulation and function of MPs within plaques. Here, I review the evolution of atherosclerotic plaques with respect to changes in the MP compartment from the initiation of plaque to its progression and regression, discussing the roles that recruitment, proliferation, and retention of MPs play at these different disease stages. Additional work in the future will be needed to better distinguish macrophages and DCs in plaque and to address some basic unknowns in the field, including just how cholesterol drives accumulation of macrophages in lesions to build plaques in the first place and how macrophages as major effectors of innate immunity work together with components of the adaptive immune response to drive atherosclerosis. Answers to these questions are sought with the goal in mind of reversing disease where it exists and preventing its development where it does not.

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“…3C). IL-18 is secreted after processing by activated caspase-1 and caspase-11 [40]. This occurs downstream of inflammasome activation, suggesting that injection with GLA-SE triggered the inflammasome.…”

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confidence: 99%

Squalene emulsion potentiates the adjuvant activity of the TLR4 agonist, GLA, via inflammatory caspases, IL‐18, and IFN‐γ

et al. 2014

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+T-cell induction via GLA-SE. Thus, we demonstrate that IL-18 and caspase-1/11 are components of the response to immunization with the TLR4 agonist/squalene oil-inwater based adjuvant, GLA-SE, providing implications for other adjuvants that combine oils with TLR agonists. Additional supporting information may be found in the online version of this article at the publisher's web-site Keywords: Adjuvants IntroductionVaccines rely on triggering the innate immune system to generate protective immunity. Many empirically established vaccines serendipitously contain molecules known as pathogen-associated molecular patterns (PAMPs) that engage host-germline encoded receptors, e.g. TLRs, which contribute to their immunogenicity Correspondence: Dr. Anthony L. Desbien e-mail: Anthony.Desbien@IDRI.org [1]. In the case where antigen preparations alone fail to be immunogenic, extrinsic adjuvants, such as alum or oil emulsions, are added to make vaccines effective. Such extrinsic adjuvants were empirically developed and despite their use in billions of vaccine doses, their mechanisms of action are not completely understood [2,3]. Knowledge of the salient attributes of empirical adjuvants would facilitate the design of the next generation of vaccines.In order to function as adjuvants, deliberately incorporated PAMPs require proper formulation [4,5]. For unknown reasons, squalene oil-in-water emulsions (SEs), such as AS02 and MF59, C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 408Anthony L. Desbien et al. Eur. J. Immunol. 2015. 45: 407-417 are excellent formulations for TLR agonists, greatly enhancing the magnitude and quality of the immune response [6][7][8][9][10][11]. While it is clear that squalene emulsions by themselves are potent adjuvants, exactly how they engage the immune system or cooperate with TLR agonists is unclear. The commercial product MF59 is the prototypical squalene adjuvant. MF59 has been shown to activate the innate immune system, alter antigen presentation, and enhance humoral responses [3,[12][13][14]. While these attributes are ostensibly useful for generation of immunity, the specific components of the immune system triggered by squalene emulsions remain to be elucidated. The inflammasome is a pathogen recognition system required for protection against many diseases [15]. Engagement of the inflammasome occurs by diverse stimuli including pathogenand host-derived molecules. Known triggers include cytoplasmic dsDNA as well as aberrantly localized host-derived molecules, referred to as danger-associated molecular patterns [16]. In particular, extracellular ATP acts as a danger-associated molecular pattern, and has been recently demonstrated to contribute to activity of MF59, suggesting that MF59 acts via the inflammasome [17]. Further, the antibody response to immunization with MF59 has been linked to the adapter protein ASC, a component of the inflammasome, but not caspase-1 or NLRP3 (where NLR is nod-like receptor), indicating that adjuvant activity of MF59 is mediated by stil...

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Revisiting Caspase-11 Function in Host Defense

Cited by 30 publications

References 44 publications

Effects of bone marrow mesenchymal stem cells on the cardiac function and immune system of mice with endotoxemia

Effects of bone marrow mesenchymal stem cells on the cardiac function and immune system of mice with endotoxemia

Mechanisms That Regulate Macrophage Burden in Atherosclerosis

Squalene emulsion potentiates the adjuvant activity of the TLR4 agonist, GLA, via inflammatory caspases, IL‐18, and IFN‐γ

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