Gene Deletion of <i>Gabarap</i> Enhances Nlrp3 Inflammasome-Dependent Inflammatory Responses

Zhang, Zhi Rong; Xu, Xiaozheng; Ma, Jian; Wu, Jianfeng; Wang, Yanhai; Zhou, Rongbin; Han, Jiahuai

doi:10.4049/jimmunol.1202628

Cited by 36 publications

(36 citation statements)

References 42 publications

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“…Inflammatory cells (e.g. macrophages, neutrophils) are well-documented sources of IL-1β production [45], [47]. In addition to these inflammatory cells, our data indicate that CFs are important cells within the heart that produce IL-1β.…”

Section: Discussionmentioning

confidence: 65%

Cardiac Fibroblasts Contribute to Myocardial Dysfunction in Mice with Sepsis: The Role of NLRP3 Inflammasome Activation

Zhang

Kao

et al. 2014

PLoS ONE

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Myocardial contractile dysfunction in sepsis is associated with the increased morbidity and mortality. Although the underlying mechanisms of the cardiac depression have not been fully elucidated, an exaggerated inflammatory response is believed to be responsible. Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome is an intracellular platform that is involved in the maturation and release of interleukin (IL)-1β. The aim of the present study is to evaluate whether sepsis activates NLRP3 inflammasome/caspase-1/IL-1β pathway in cardiac fibroblasts (CFs) and whether this cytokine can subsequently impact the function of cardiomyocytes (cardiac fibroblast-myocyte cross-talk). We show that treatment of CFs with lipopolysaccharide (LPS) induces upregulation of NLRP3, activation of caspase-1, as well as the maturation (activation) and release of IL-1β. In addition, the genetic (small interfering ribonucleic acid [siRNA]) and pharmacological (glyburide) inhibition of the NLRP3 inflammasome in CFs can block this signaling pathway. Furthermore, the inhibition of the NLRP3 inflammasome in cardiac fibroblasts ameliorated the ability of LPS-chalenged CFs to impact cardiomyocyte function as assessed by intracellular cyclic adenosine monophosphate (cAMP) responses in cardiomyocytes. Salient features of this the NLP3 inflammasome/ caspase-1 pathway were confirmed in in vivo models of endotoxemia/sepsis. We found that inhibition of the NLRP3 inflammasome attenuated myocardial dysfunction in mice with LPS and increased the survival rate in mice with feces-induced peritonitis. Our results indicate that the activation of the NLRP3 inflammasome in cardiac fibroblasts is pivotal in the induction of myocardial dysfunction in sepsis.

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Section: Discussionmentioning

confidence: 65%

Cardiac Fibroblasts Contribute to Myocardial Dysfunction in Mice with Sepsis: The Role of NLRP3 Inflammasome Activation

Zhang

Kao

et al. 2014

PLoS ONE

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“…In addition, many studies have been carried in vitro using cells that are deficient in NLRP3 inflammasome components. [39][40][41] The availability of NLRP3 knockout mice has provided an animal model to study regulation of NLRP3 during infections 42,43 and in autoimmune diseases. 44,45 There are a few studies that suggest that the NLRP3 inflammasome has a role in the CNS.…”

Section: The Nlrp3 Inflammasomementioning

confidence: 99%

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

Vaccari¹,

Dietrich²,

Keane

2014

J Cereb Blood Flow Metab

292

227

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The inflammasome is an intracellular multiprotein complex involved in the activation of caspase-1 and the processing of the proinflammatory cytokines interleukin-1b (IL-1b) and IL-18. The inflammasome in the central nervous system (CNS) is involved in the generation of an innate immune inflammatory response through IL-1 cytokine release and in cell death through the process of pyroptosis. In this review, we consider the different types of inflammasomes (NLRP1, NLRP2, NLRP3, and AIM2) that have been described in CNS cells, namely neurons, astrocytes, and microglia. Importantly, we focus on the role of the inflammasome after brain and spinal cord injury and cover the potential activators of the inflammasome after CNS injury such as adenosine triphosphate and DNA, and the therapeutic potential of targeting the inflammasome to improve outcomes after CNS trauma.

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“…[9][10][11][12] When mitophagy is impaired, the increase of damaged mitochondria caused by immune stimulators results in the generation of mitochondrial ROS (reactive oxygen species) and release of mitochondrial DNA, which induces hyperactivation of the NLRP3 inflammasome, and in turn leads to over-inflammation, tissue injury and increased mortality in the host. 9,10,12,13 Although a number of mitophagy-related factors have been identified, detailed mechanisms by which they take action are still largely unknown. Recent studies on mitophagy in mammalian cell studies reveal that signal-dependent removal of damaged mitochondria by mitophagy requires 2 steps.…”

Section: Introductionmentioning

confidence: 99%

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

et al. 2016

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Proper regulation of mitophagy for mitochondrial homeostasis is important in various inflammatory diseases. However, the precise mechanisms by which mitophagy is activated to regulate inflammatory responses remain largely unknown. The NLRP3 (NLR family, pyrin domain containing 3) inflammasome serves as a platform that triggers the activation of CASP1 (caspase 1) and secretion of proinflammatory cytokines. Here, we demonstrate that SESN2 (sestrin 2), known as stress-inducible protein, suppresses prolonged NLRP3 inflammasome activation by clearance of damaged mitochondria through inducing mitophagy in macrophages. SESN2 plays a dual role in inducing mitophagy in response to inflammasome activation. First, SESN2 induces "mitochondrial priming" by marking mitochondria for recognition by the autophagic machinery. For mitochondrial preparing, SESN2 facilitates the perinuclear-clustering of mitochondria by mediating aggregation of SQSTM1 (sequestosome 1) and its binding to lysine 63 (Lys63)-linked ubiquitins on the mitochondrial surface. Second, SESN2 activates the specific autophagic machinery for degradation of primed mitochondria via an increase of ULK1 (unc-51 like kinase 1) protein levels. Moreover, increased SESN2 expression by extended LPS (lipopolysaccharide) stimulation is mediated by NOS2 (nitric oxide synthase 2, inducible)-mediated NO (nitric oxide) in macrophages. Thus, Sesn2-deficient mice displayed defective mitophagy, which resulted in hyperactivation of inflammasomes and increased mortality in 2 different sepsis models. Our findings define a unique regulatory mechanism of mitophagy activation for immunological homeostasis that protects the host from sepsis.

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Gene Deletion of Gabarap Enhances Nlrp3 Inflammasome-Dependent Inflammatory Responses

Cited by 36 publications

References 42 publications

Cardiac Fibroblasts Contribute to Myocardial Dysfunction in Mice with Sepsis: The Role of NLRP3 Inflammasome Activation

Cardiac Fibroblasts Contribute to Myocardial Dysfunction in Mice with Sepsis: The Role of NLRP3 Inflammasome Activation

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

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