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Flagellin attenuates experimental sepsis in a macrophage-dependent manner.

ABSTRACT: BACKGROUND:Sepsis is the leading cause of death among critically ill patients, and no specific therapeutic agent is currently approved for the treatment of sepsis. METHODS:We assessed the effects of flagellin administration on survival, bacterial burden, and tissue injury after sepsis. In addition, we examined the effects on phagocytosis and bacterial killing in monocytes/macrophages. RESULTS:Therapeutic administration of flagellin increased bacterial clearance, decreased organ inflammation and injury, and reduced immune cell apoptosis after experimental sepsis, in a Toll-like receptor 5 (TLR5)-dependent manner. Macrophages, but not neutrophils, mediated the beneficial effects of flagellin on experimental sepsis, and flagellin induced macrophage polarization into M1 in septic mice. Flagellin treatment could directly enhance phagocytosis and bacterial killing of macrophages, but not neutrophils. Subsequent studies demonstrated that flagellin could promote phagosome formation and increase reactive oxygen species (ROS) levels in macrophages. Finally, we found that the expression of TLR5 was significantly elevated on the surface of circulating monocytes, but not neutrophils, from patients with sepsis. Higher expression levels of TLR5 on monocytes were associated with increased mortality, documented bacteremia, and higher Sequential Organ Failure Assessment scores of the septic patients. Moreover, flagellin treatment rescued the impaired phagocytosis and bacterial killing ability of monocytes/macrophages from patients who died of sepsis. CONCLUSIONS:These novel findings not only established the potential value of application of flagellin as an immunoadjuvant in treating sepsis, but also provided new insights into targeted therapeutic strategy on the basis of monocyte TLR5 expression in septic patients.

SUBMITTER: Yang X

PROVIDER: S-EPMC6446324 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Flagellin attenuates experimental sepsis in a macrophage-dependent manner.

Yang Xiaoliang X Yin Yibing Y Yan Xingxing X Yu Zebo Z Liu Yi Y Cao Ju J

Critical care (London, England) 20190403 1

<h4>Background</h4>Sepsis is the leading cause of death among critically ill patients, and no specific therapeutic agent is currently approved for the treatment of sepsis.<h4>Methods</h4>We assessed the effects of flagellin administration on survival, bacterial burden, and tissue injury after sepsis. In addition, we examined the effects on phagocytosis and bacterial killing in monocytes/macrophages.<h4>Results</h4>Therapeutic administration of flagellin increased bacterial clearance, decreased o ...[more]

PMID: 30944018

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Project description:BackgroundOxidative stress and neuroinflammation are considered the major central events in the process of Parkinson's disease (PD). Nrf2 is a key regulator of endogenous defense systems. New finds have contacted activation of Nrf2 signaling with anti-inflammatory activities. Therefore, the outstanding inhibition of neuroinflammation or potent Nrf2 signaling activation holds a promising strategy for PD treatment. Icariin (ICA), a natural compound derived from Herba Epimedii, presents a number of pharmacological properties, including anti-oxidation, anti-aging and anti-inflammatory actions. Recent studies have confirmed ICA exerted neuroprotection against neurodegenerative disorders. However, the underlying mechanisms were not fully elucidated.MethodsIn the present study, mouse nigral stereotaxic injection of 6-hydroxydopamine (6-OHDA)-induced PD model was performed to investigate ICA-conferred dopamine (DA) neuroprotection. In addition, adult Nrf2 knockout mice and primary rat midbrain neuron-glia co-culture was applied to elucidate whether ICA-exerted neuroprotection was through an Nrf2-dependent mechanism.ResultsResults indicated that ICA attenuated 6-OHDA-induced DA neurotoxicity and glial cells-mediated neuroinflammatory response. Furtherly, activation of Nrf2 signaling pathway in glial cells participated in ICA-produced neuroprotection, as revealed by the following observations. First, ICA enhanced Nrf2 signaling activation in 6-OHDA-induced mouse PD model. Second, ICA failed to generate DA neuroprotection and suppress glial cells-mediated pro-inflammatory factors production in Nrf2 knockout mice. Third, ICA exhibited neuroprotection in primary neuron-glia co-cultures but not in neuron-enriched cultures (without glial cells presence). Either, ICA-mediated neuroprotection was not discerned after Nrf2 siRNA treatment in neuron-glia co-cultures.ConclusionsOur findings identify that ICA attenuated glial cells-mediated neuroinflammation and evoked DA neuroprotection via an Nrf2-dependent manner.

Project description:Sepsis patients are at increased risk for hospital-acquired pulmonary infections, potentially due to postseptic immunosuppression known as the compensatory anti-inflammatory response syndrome (CARS). CARS has been attributed to leukocyte dysfunction, with an unclear role for endothelial cells. The pulmonary circulation is lined by an endothelial glycocalyx, a heparan sulfate-rich layer essential to pulmonary homeostasis. Heparan sulfate degradation occurs early in sepsis, leading to lung injury. Endothelial synthesis of new heparan sulfates subsequently allows for glycocalyx reconstitution and endothelial recovery. We hypothesized that remodeling of the reconstituted endothelial glycocalyx, mediated by alterations in the endothelial machinery responsible for heparan sulfate synthesis, contributes to CARS. Seventy-two hours after experimental sepsis, coincident with glycocalyx reconstitution, mice demonstrated impaired neutrophil and protein influx in response to intratracheal lipopolysaccharide (LPS). The postseptic reconstituted glycocalyx was structurally remodeled, with enrichment of heparan sulfate disaccharides sulfated at the 6-O position of glucosamine. Increased 6-O-sulfation coincided with loss of endothelial sulfatase-1 (Sulf-1), an enzyme that specifically removes 6-O-sulfates from heparan sulfate. Intravenous administration of Sulf-1 to postseptic mice restored the pulmonary response to LPS, suggesting that loss of Sulf-1 was necessary for postseptic suppression of pulmonary inflammation. Endothelial-specific knockout mice demonstrated that loss of Sulf-1 was not sufficient to induce immunosuppression in non-septic mice. Knockdown of Sulf-1 in human pulmonary microvascular endothelial cells resulted in downregulation of the adhesion molecule ICAM-1. Taken together, our study indicates that loss of endothelial Sulf-1 is necessary for postseptic suppression of pulmonary inflammation, representing a novel endothelial contributor to CARS.

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Flagellin attenuates experimental sepsis in a macrophage-dependent manner.

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Flagellin attenuates experimental sepsis in a macrophage-dependent manner.

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