??-Arrestins Regulate Lipopolysaccharide (Lps)-Induced Signaling and Proinflammatory Gene Expression

Fan, Huishou; Luttrell, Louis M.; Zingarelli, Basilia; Senn, Joseph J.; Tempel, G; Halushka, P. V.; Cook, James A.

doi:10.1097/00024382-200606001-00024

Cited by 8 publications

(13 citation statements)

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“…Afterward, other findings indicated that the functions of b-arrestins are pleiotropic (35,36). Nevertheless, we found that b-arrestin1 had no effect on IL-6 and pro-IL-1b production, but it regulated IL-1b secretion by regulating inflammasome activation.…”

Section: Discussioncontrasting

confidence: 47%

β-arrestin1 Is Critical for the Full Activation of NLRP3 and NLRC4 Inflammasomes

Mao

Chen

Wang

et al. 2015

The Journal of Immunology

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Inflammasomes are multiprotein complexes that trigger the activation of caspase-1 and the maturation of IL-1β, which are critical for inflammation and control of pathogen infection. Although the function of inflammasomes in immune response and disease development is well studied, the molecular mechanism by which inflammasomes are activated and assembled remains largely unknown. In this study, we found that β-arrestin1, a key regulator of the G protein–coupled receptor signaling pathway, was required for nucleotide-binding domain and leucine-rich repeat containing (NLR) family pyrin domain–containing 3 (NLRP3) and NLR family CARD domain–containing protein 4 (NLRC4) inflammasome–mediated IL-1β production and caspase-1 activation, but it had no effect on absent in melanoma 2 (AIM2) inflammasome activation. Moreover, apoptosis-associated speck-like protein containing a CARD (ASC) pyroptosome, which is ASC aggregation mediating caspase-1 activation, was also impaired in β-arrestin1–deficient macrophages upon NLRP3 or NLRC4, but not AIM2 inflammasome activation. Mechanistic study revealed that β-arrestin1 specifically interacted with NLRP3 and NLRC4 and promoted their self-oligomerization. In vivo, in a monosodium urate crystal (MSU)-induced NLRP3-dependent peritonitis model, MSU-induced IL-1β production and neutrophil flux were significantly reduced in β-arrestin1 knockout mice. Additionally, β-arrestin1 deficiency rescued the weight loss of mice upon log-phase Salmonella typhimurium infection, with less IL-1β production. Taken together, our results indicate that β-arrestin1 plays a critical role in the assembly and activation of two major canonical inflammasomes, and it may provide a new therapeutic target for inflammatory diseases.

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Section: Discussioncontrasting

confidence: 47%

β-arrestin1 Is Critical for the Full Activation of NLRP3 and NLRC4 Inflammasomes

Mao

Chen

Wang

et al. 2015

The Journal of Immunology

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“…The LPA acyltransferase inhibitor lysofylline attenuated LPA degradation and protected lung leak in vivo (59), and LPA enhanced barrier function in corneal endothelial cells (60). Furthermore, a recent study from Fan et al (44) showed that the administration of LPA has an anti-inflammatory effect in murine models of pulmonary inflammatory disease. Intravenous injection of LPA attenuated bacterial endotoxin-induced plasma tumor necrosis factor-␣ production and myeloperoxidase activity in the lung of mice suggesting that exogenously administered LPA plays a protective role in pulmonary inflammatory diseases (44).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a recent study from Fan et al (44) showed that the administration of LPA has an anti-inflammatory effect in murine models of pulmonary inflammatory disease. Intravenous injection of LPA attenuated bacterial endotoxin-induced plasma tumor necrosis factor-␣ production and myeloperoxidase activity in the lung of mice suggesting that exogenously administered LPA plays a protective role in pulmonary inflammatory diseases (44). This study supports the potential role LPA and LPA analogs as novel therapeutic agents against endotoxin-induced pulmonary epithelial barrier disruption.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that LPA may play a protective role in lung disease by stimulating an innate immune response while simultaneously attenuating the adaptive immune response. Furthermore, intravenous injection with LPA attenuated bacterial endotoxin-induced plasma tumor necrosis factor-␣ production and myeloperoxidase activity in the lungs of mice (44), suggesting an anti-inflammatory role for LPA in a murine model of sepsis.…”

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confidence: 93%

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Lysophosphatidic Acid Enhances Pulmonary Epithelial Barrier Integrity and Protects Endotoxin-induced Epithelial Barrier Disruption and Lung Injury

Usatyuk

et al. 2009

Journal of Biological Chemistry

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Lysophosphatidic acid (LPA), a bioactive phospholipid, induces a wide range of cellular effects, including gene expression, cytoskeletal rearrangement, and cell survival. We have previously shown that LPA stimulates secretion of pro-and antiinflammatory cytokines in bronchial epithelial cells. This study provides evidence that LPA enhances pulmonary epithelial barrier integrity through protein kinase C (PKC) ␦-and -mediated

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“…This role as a critical scaffolding molecule extends ␤-arrestins' capability in modulating inflammation beyond GPCRs to non-GPCRs, such as Toll-like receptors (24,25,30). Studies have shown that the role of ␤-arrestins in inflammation is highly context dependent and that, depending on the stimulus and disease model, ␤-arrestins can either mediate or inhibit inflammation (11,12,31,32). In this regard, we recently demonstrated that ␤-arrestin-2 (␤-arr2) promotes an increase in systemic levels of gamma interferon (IFN-␥) and other cytokines in the endotoxemia model (11) whereas it inhibits adenovirus-induced innate responses (33).…”

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confidence: 96%

Gene Dosage-Dependent Negative Regulatory Role of β-Arrestin-2 in Polymicrobial Infection-Induced Inflammation

et al. 2013

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␤-arrestin-2 (␤-arr2) is a scaffolding protein of the arrestin family with a wide variety of cellular functions. Recent studies have demonstrated differential roles for ␤-arr2 in inflammation following endotoxemia and cecal ligation and puncture (CLP) models of sepsis. Because CLP-induced inflammation involves response to fecal contents and necrotic cecum in addition to microbial challenge, in this study, we examined the role of ␤-arr2 in an exclusively polymicrobial infection (PMI) model. In addition, we examined the role of gene dosage of ␤-arr2 in polymicrobial sepsis. Our studies demonstrate that ␤-arr2 is a negative regulator of systemic inflammation in response to polymicrobial infection and that one allele is sufficient for this process. Our results further reveal that loss of ␤-arr2 leads to increased neutrophil sequestration and overt inflammation specifically in the lungs following polymicrobial infection. Consistent with this, specific NF-B and mitogen-activated protein kinase (MAPK) signaling pathways were differentially activated in the ␤-arr2 knockout (KO) mice lungs compared to the wild type (WT) following PMI. Associated with enhanced inflammation in the KO mice, PMI-induced mortality was also significantly higher in KO mice than in WT mice. To understand the differential role of ␤-arr2 in different sepsis models, we used cell culture systems to evaluate inflammatory cytokine production following endotoxin and polymicrobial stimulation. Our results demonstrate cell-type-as well as stimulus-specific roles for ␤-arr2 in inflammation. Taken together, our results reveal a negative regulatory role for ␤-arr2 in polymicrobial infection-induced inflammation and further demonstrate that one allele of ␤-arr2 is sufficient to mediate most of these effects.

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??-Arrestins Regulate Lipopolysaccharide (Lps)-Induced Signaling and Proinflammatory Gene Expression

Cited by 8 publications

References 0 publications

β-arrestin1 Is Critical for the Full Activation of NLRP3 and NLRC4 Inflammasomes

β-arrestin1 Is Critical for the Full Activation of NLRP3 and NLRC4 Inflammasomes

Lysophosphatidic Acid Enhances Pulmonary Epithelial Barrier Integrity and Protects Endotoxin-induced Epithelial Barrier Disruption and Lung Injury

Gene Dosage-Dependent Negative Regulatory Role of β-Arrestin-2 in Polymicrobial Infection-Induced Inflammation

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