Sustained Immunoparalysis in Endotoxin-Tolerized Monocytic Cells

Weisheit, Christina; Klüners, Alexandra; Wild, Lennart; Casalter, Alexandra; Heilmann‐Heimbach, Stefanie; Sivalingam, Sugirthan; Kleiner, Jan Lukas; Ehrentraut, Stefan; Hoeft, Andreas; Frede, Stilla; Ehrentraut, Heidi

doi:10.1155/2020/8294342

Cited by 8 publications

(11 citation statements)

References 41 publications

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“…The macrophage pretreatment with olaparib prior to LPS stimulation maintains a pro-inflammatory response. It confirms the role of PARP1 in cytokine expression control that has already been published by other groups [ 31 , 34 ]. Furthermore, the involvement of PARP inhibitors that differ in the DNA binding potential showed that PARP1 extrusion from the chromatin allows for chromatin remodeling, which prevents p65 rebinding upon the following macrophage stimulation with LPS.…”

Section: Discussionsupporting

confidence: 90%

PARP Traps Rescue the Pro-Inflammatory Response of Human Macrophages in the In Vitro Model of LPS-Induced Tolerance

2021

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Secondary infections cause sepsis that lead to patient disability or death. Contact of macrophages with bacterial components (such as lipopolysaccharide—LPS) activates the intracellular signaling pathway downstream of Toll-like receptors (TLR), which initiate an immune proinflammatory response. However, the expression of nuclear factor-kappa B (NF-κB)-dependent proinflammatory cytokines significantly decreases after single high or multiple LPS stimulations. Knowing that poly(ADP-ribose) polymerase-1 (PARP1) serves as a cofactor of NF-κB, we aimed to verify a hypothesis of the possible contribution of PARP1 to the development of LPS-induced tolerance in human macrophages. Using TNF-α mRNA expression as a readout, we demonstrate that PARP1 interaction with the TNF-α promoter, controls macrophage immunoparalysis. We confirm that PARP1 is extruded from the gene promoter, whereas cell pretreatment with Olaparib maintains macrophage responsiveness to another LPS treatment. Furthermore, cell pretreatment with proteasome inhibitor MG132 completely abrogates the effect of Olaparib, suggesting that PARP1 acts with NF-κB in the same regulatory pathway, which controls pro-inflammatory cytokine transcription. Mechanistically, PARP1 trapping allows for the re-rebinding of p65 to the TNF-α promoter in LPS-stimulated cells. In conclusion, PARP traps prevent PARP1 extrusion from the TNF-α promoter upon macrophage stimulation, thereby maintaining chromatin responsiveness of TLR activation, allowing for the re-binding of p65 and TNF-α transcription.

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Section: Discussionsupporting

confidence: 90%

PARP Traps Rescue the Pro-Inflammatory Response of Human Macrophages in the In Vitro Model of LPS-Induced Tolerance

2021

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“…The mouse model of LPS-induced sepsis is well established, and mirrors gram-negative bacterial infections in a standardized manner. 21,22 LPS is a potent activator of inflammatory responses, leading to cytokine release and leukocyte recruitment. 23 In the peritoneal cavity, the resident leukocyte population is composed of 45%-90% macrophages, 2%-6% dendritic cells, and less than 5% neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Vancomycin and daptomycin modulate the innate immune response in a murine model of LPS-induced sepsis

Muenster

Zschernack

Dierig³

et al. 2021

Int J Immunopathol Pharmacol

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Sepsis is a leading cause of death worldwide, despite the use of multimodal therapies. Common antibiotic regimens are being affected by a rising number of multidrug-resistant pathogens, and new therapeutic approaches are therefore needed. Antibiotics have immunomodulatory properties which appear to be beneficial in the treatment of sepsis. We hypothesized that the last-resort antibiotics vancomycin (VAN) and daptomycin (DMC) modulate cell migration, phagocytosis, and protein cytokine levels in a murine model of lipopolysaccharide (LPS)-induced sepsis. Ten to twelve-week-old C57BL/6 mice ( n = 4–6 animals per group) were stimulated with LPS for 20 h, followed by the administration of VAN or DMC. The outcome parameters were leukocyte accumulation and effector function. Quantification of the immune cells in the peritoneal lavage was performed using flow cytometry analysis. Phagocytosis was measured using pHrodo E. coli BioParticles. The response of the cytokines TNFα, IL-6, and IL-10 was measured in vitro using murine peritoneal macrophages stimulated with LPS and VAN or DMC. VAN decreased both the peritoneal macrophage and the dendritic cell populations following LPS stimulation. DMC reduced the dendritic cell population in the peritoneal cavity in LPS-infected mice. Both antibiotics increased the phagocytic activity in peritoneal macrophages, but this effect was diminished in response to LPS. Phagocytosis of dendritic cells was increased in LPS-infected animals treated with VAN. VAN and DMC differently modulated the levels of pro-and anti-inflammatory cytokines. In a murine model of LPS-induced sepsis, VAN and DMC exhibit immunomodulatory effects on cells involved in innate immunity. The question of whether these antibiotics exhibit synergistic effects in the treatment of septic patients, beyond their bactericidal properties, should be further evaluated in future studies.

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“…Several metabolic defects have been described in patients with sepsis, for example, decreased glycolysis and oxygen consumption in monocytes or a dysfunctional mammalian target of the rapamycin (mTOR) pathway [ 74 ]. Weisheit et al [ 75 ] observed differential methylation of CpG sites related to metabolic activity in human peripheral blood mononuclear cells (PBMCs) 18 h after septic challenge.…”

Section: Innate Immunity In Sakimentioning

confidence: 99%

“…The decreased capacity of monocytes collected from patients with sepsis to release proinflammatory cytokines in response to LPS, TLR agonists, or various bacterial compounds can lead to sepsis-induced immunotolerance. Similarly, prestimulation of monocytes with high doses of LPS can induce immunoparalysis [ 75 ]. Therefore, it seems that a cytokine storm at the beginning of sepsis may cause the loss of specific epigenetic marks at promoters of proinflammatory genes in monocytes or macrophages, promoting their tolerogenic state.…”

Section: Innate Immunity In Sakimentioning

confidence: 99%

Kynurenine Pathway—An Underestimated Factor Modulating Innate Immunity in Sepsis-Induced Acute Kidney Injury?

Krupa

Pawlak

2022

Cells

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Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and it accounts for about half of the cases of acute kidney injury (AKI). Although sepsis is the most frequent cause of AKI in critically ill patients, its pathophysiological mechanisms are not well understood. Sepsis has the ability to modulate the function of cells belonging to the innate immune system. Increased activity of indoleamine 2,3-dioxygenase 1 (IDO1) and production of kynurenines are the major metabolic pathways utilized by innate immunity cells to maintain immunological tolerance. The activation of the kynurenine pathway (KP) plays a dual role in sepsis—in the early stage, the induction of IDO1 elicits strong proinflammatory effects that may lead to tissue damage and septic shock. Afterwards, depletion of tryptophan and production of kynurenines contribute to the development of immunosuppression that may cause the inability to overpower opportunistic infections. The presented review provides available data on the various interdependencies between elements of innate immunity and sepsis-induced AKI (SAKI) with particular emphasis on the immunomodulatory significance of KP in the above processes. We believe that KP activation may be one of the crucial, though underestimated, components of a deregulated host response to infection during SAKI.

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Sustained Immunoparalysis in Endotoxin-Tolerized Monocytic Cells

Cited by 8 publications

References 41 publications

PARP Traps Rescue the Pro-Inflammatory Response of Human Macrophages in the In Vitro Model of LPS-Induced Tolerance

PARP Traps Rescue the Pro-Inflammatory Response of Human Macrophages in the In Vitro Model of LPS-Induced Tolerance

Vancomycin and daptomycin modulate the innate immune response in a murine model of LPS-induced sepsis

Kynurenine Pathway—An Underestimated Factor Modulating Innate Immunity in Sepsis-Induced Acute Kidney Injury?

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