Pre-treatment with low-dose endotoxin prolongs survival from experimental lethal endotoxic shock: Benefit for lethal peritonitis by Escherichia coli

Kopanakis, Konstantinos; Tzepi, Ira-Maria; Pistiki, Aikaterini; Carrer, Dionyssia-Pinelopi; Netea, Mihai G.; Georgitsi, Marianna; Lymperi, Maria; Droggiti, Dionyssia-Irini; Liakakos, Theodore; Machairas, Anastasios; Giamarellos‐Bourboulis, Evangelos J.

doi:10.1016/j.cyto.2013.03.028

Cited by 25 publications

(28 citation statements)

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“…The results described above showed that the NFI-A conditional knockout mouse survivors do not develop immunosuppression and that Gr1 ϩ CD11b ϩ cells can differentiate into immunocompetent macrophages and dendritic cells and likely have immunocompetent CD4 ϩ T lymphocytes. Sepsis without infection can be partially mimicked by systematic administration of Gram-negative bacterial LPS, which, in mice, nonhuman primates, and humans (25), rapidly activates innate immune cells to generate proinflammatory cytokines such as TNF-␣ and IL-6. After LPS stimulation in vivo, cells and organs rapidly enter a state of tolerance of endotoxin, with combined organ failure and immunosuppression (26,27).…”

Section: Nfi-a Promotes Sepsis Immunosuppressionmentioning

confidence: 99%

Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival

et al. 2017

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Myeloid progenitor-derived suppressor cells (MDSCs) arise from myeloid progenitors and suppress both innate and adaptive immunity. MDSCs expand during the later phases of sepsis in mice, promote immunosuppression, and reduce survival. Here, we report that the myeloid differentiation-related transcription factor nuclear factor I-A (NFI-A) controls MDSC expansion during sepsis and impacts survival. Unlike MDSCs, myeloid cells with conditional deletion of the Nfia gene normally differentiated into effector cells during sepsis, cleared infecting bacteria, and did not express immunosuppressive mediators. In contrast, ectopic expression of NFI-A in myeloid progenitors from NFI-A myeloid cell-deficient mice impeded myeloid cell maturation and promoted immune repressor function. Importantly, surviving septic mice with conditionally deficient NFI-A myeloid cells were able to respond to challenge with bacterial endotoxin by mounting an acute inflammatory response. Together, these results support the concept of NFI-A as a master molecular transcriptome switch that controls myeloid cell differentiation and maturation and that malfunction of this switch during sepsis promotes MDSC expansion that adversely impacts sepsis outcome.KEYWORDS inflammation, sepsis immunosuppression, MDSCs, NFI-A, sepsis M yeloid progenitor-derived suppressor cells (MDSCs) represent a heterogenous population of immature myeloid cells that includes progenitors and precursors of monocytes/macrophages, granulocytes, and dendritic cells (1-3). MDSCs are generated under a variety of inflammatory and infection conditions (1, 2) and are best characterized by their immunosuppressive functions (4-6). They may also promote persistent inflammation and chronic infection with catabolism during chronic sepsis (7). MDSCs suppress both innate and adaptive immunity via production of immunosuppressive mediators and inhibition of T cell proliferation and activation (3,4,8). Phenotypically, murine MDSCs coexpress the myeloid differentiation markers Gr1 and CD11b, similarly to the Gr1 ϩ CD11b ϩ myeloid progenitors that arise under normal physiological conditions (2, 9). Unlike the immunosuppressive Gr1 ϩ CD11b ϩ cells (i.e., MDSCs), normal Gr1 ϩ CD11b ϩ cells can differentiate into competent innate immune cells (3). Elimination of MDSCs in tumor-bearing mice enhances antitumor immunity (10). Since MDSCs are "immature" cells that deviate from the standard path of differentiation, it has been suggested that arrested myeloid cell differentiation and maturation may be responsible for MDSC generation and immunorepression (2, 6). How immature myeloid cells lose their ability to differentiate and instead generate MDSCs remains unclear. Some studies, however, have suggested that MDSCs retain their potential to differentiate and mature but are trapped in a MDSC phenotype in the environmental milieu of chronic inflammation or growing tumors (1). In support of this, Kusmartsev et al. (10) reported that MDSCs from tumor-bearing mice could differentiate into macrophages and...

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Section: Nfi-a Promotes Sepsis Immunosuppressionmentioning

confidence: 99%

Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival

et al. 2017

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“…Animals pretreated with a low dose of endotoxin have a markedly reduced mortality when rechallenged with a normally “lethal” dose of endotoxin [24, 25], a phenomenon termed “endotoxin tolerance.” In humans, endotoxin tolerance was developed during five consecutive LPS administrations as demonstrated by the attenuated release of proinflammatory cytokines on the fifth day and was associated with less leukocyte and endothelial activation [26]. This refractoriness to LPS is considered to be an adaptation to prevent overstimulation from the continuous exposure to LPS [27, 28].…”

Section: Discussionmentioning

confidence: 99%

Upregulating Nonneuronal Cholinergic Activity Decreases TNF Release from Lipopolysaccharide-Stimulated RAW264.7 Cells

Lv¹,

Hu²,

Lu³

et al. 2014

Mediators of Inflammation

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Nonneuronal cholinergic system plays a primary role in maintaining homeostasis. It has been proved that endogenous neuronal acetylcholine (ACh) could play an anti-inflammatory role, and exogenous cholinergic agonists could weaken macrophages inflammatory response to lipopolysaccharide (LPS) stimulation through activation of α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR). We assumed that nonneuronal cholinergic system existing in macrophages could modulate inflammation through autocrine ACh and expressed α7nAChR on the cells. Therefore, we explored whether LPS continuous stimulation could upregulate the nonneuronal cholinergic activity in macrophages and whether increasing autocrine ACh could decrease TNF release from the macrophages. The results showed that, in RAW264.7 cells incubated with LPS for 20 hours, the secretion of ACh was significantly decreased at 4 h and then gradually increased, accompanied with the enhancement of α7nAChR expression level. The release of TNF was greatly increased from RAW264.7 cells at 4 h and 8 h exposure to LPS; however, it was suppressed at 20 h. Upregulating choline acetyltransferase (ChAT) expression through ChAT gene transfection could enhance ACh secretion and reduce TNF release from the infected RAW264. 7cells. The results indicated that LPS stimulation could modulate the activity of nonneuronal cholinergic system of RAW264.7 cells. Enhancing autocrine ACh production could attenuate TNF release from RAW264.7 cells.

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“…Although gram-negative bacteria carry a wide variety of pathogen-associated molecular patterns (PAMPs) that can interact with Toll-like receptors (TLRs) embedded on circulating monocytes and tissue macrophages, their LPS is the best studied PAMP. Exposure to LPS leads to endotoxin tolerance whereby a second exposure to LPS elicits blurred cytokine production [12–14]. Circulating PBMCs of both survivors and non-survivors have defective cytokine production on day 1 after exposure to LPS, representing signs of LPS tolerance.…”

Section: Discussionmentioning

confidence: 99%

Decreased cytokine production by mononuclear cells after severe gram-negative infections: early clinical signs and association with final outcome

et al. 2017

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BackgroundFailure of circulating monocytes for adequate cytokine production is a trait of sepsis-induced immunosuppression; however, its duration and association with final outcome are poorly understood.MethodsWe conducted a substudy of a large randomised clinical trial. Peripheral blood mononuclear cells (PBMCs) were isolated within the first 24 h from the onset of systemic inflammatory response syndrome in 95 patients with microbiologically confirmed or clinically suspected gram-negative infections. Isolation was repeated on days 3, 7 and 10. PBMCs were stimulated for cytokine production. The study endpoints were the differences between survivors and non-survivors, the persistence of immunosuppression, and determination of admission clinical signs that can lead to early identification of the likelihood of immunosuppression.ResultsPBMCs of survivors produced significantly greater concentrations of tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, IL-10, interferon-γ and granulocyte-macrophage colony-stimulating factor after day 3. Using ROC analysis, we found that TNF-α production less than 250 pg/ml after lipopolysaccharide stimulation on day 3 could discriminate patients from healthy control subjects; this was associated with a 5.18 OR of having an unfavourable outcome (p = 0.046). This trait persisted as long as day 10. Logistic regression analysis showed that cardiovascular failure on admission was the only independent predictor of defective TNF-α production on day 3.ConclusionsDefective TNF-α production is a major trait of sepsis-induced immunosuppression. It is associated with significant risk for unfavourable outcome and persists until day 10. Cardiovascular failure on admission is predictive of defective TNF-α production during follow-up.Trial registrationClinicalTrials.gov identifier: NCT01223690. Registered on 18 October 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1625-1) contains supplementary material, which is available to authorized users.

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Pre-treatment with low-dose endotoxin prolongs survival from experimental lethal endotoxic shock: Benefit for lethal peritonitis by Escherichia coli

Cited by 25 publications

References 16 publications

Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival

Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival

Upregulating Nonneuronal Cholinergic Activity Decreases TNF Release from Lipopolysaccharide-Stimulated RAW264.7 Cells

Decreased cytokine production by mononuclear cells after severe gram-negative infections: early clinical signs and association with final outcome

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