Processing Body Formation Limits Proinflammatory Cytokine Synthesis in Endotoxin-Tolerant Monocytes and Murine Septic Macrophages

McClure, Clara; Brudecki, Laura; Yao, Zhi Q.; McCall, Charles E.; Gazzar, Mohamed El

doi:10.1159/000381915

Cited by 10 publications

(9 citation statements)

References 46 publications

(103 reference statements)

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“…Recent studies indicate that proinflammatory stimulation, including LPS/ TLR4 engagement, is associated with reprogramming of monocytes that results in diminished responses to second challenge with LPS, a condition known as endotoxin tolerance (46,47). AMPK activation has been shown to reduce proinflammatory cytokine production effectively in LPS-stimulated macrophages (38,48,49).…”

Section: Ampk Activation Prevents Macrophage Reprogramming Into An Enmentioning

confidence: 99%

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

Liu

Bone

Jiang

et al. 2015

Mol Med

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Alterations in metabolic and bioenergetic homeostasis contribute to sepsis-mediated organ injury. However, how AMP-activated protein kinase (AMPK), a major sensor and regulator of energy expenditure and production, affects development of organ injury and loss of innate capacity during polymicrobial sepsis remains unclear. In the present experiments, we found that cross-talk between the AMPK and GSK3β signaling pathways controls chemotaxis and the ability of neutrophils and macrophages to kill bacteria ex vivo. In mice with polymicrobial abdominal sepsis or more severe sepsis induced by the combination of hemorrhage and intraabdominal infection, administration of the AMPK activator metformin or the GSK3β inhibitor SB216763 reduced the severity of acute lung injury (ALI). Improved survival in metformin-treated septic mice was correlated with preservation of mitochondrial complex V (ATP synthase) function and increased amounts of ETC complex III and IV. Although immunosuppression is a consequence of sepsis, metformin effectively increased innate immune capacity to eradicate P. aeruginosa in the lungs of septic mice. We also found that AMPK activation diminished accumulation of the immunosuppressive transcriptional factor HIF-1α as well as the development of endotoxin tolerance in LPS-treated macrophages. Furthermore, AMPK-dependent preservation of mitochondrial membrane potential also prevented LPS-mediated dysfunction of neutrophil chemotaxis. These results indicate that AMPK activation reduces the severity of polymicrobial sepsis-induced lung injury and prevents the development of sepsis-associated immunosuppression.

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Section: Ampk Activation Prevents Macrophage Reprogramming Into An Enmentioning

confidence: 99%

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

Liu

Bone

Jiang

et al. 2015

Mol Med

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“…Increased cytokine secretion may be responsible for the inflammatory process, including neutrophil migration [ 21 ], and macrophages are a significant source of cytokines [ 22 ]. To further explore the anti-inflammatory action and mechanisms of FTA, we researched the effect on the cytokines expressions in zymosan-stimulated macrophages.…”

Section: Resultsmentioning

confidence: 99%

Forsythoside A Modulates Zymosan-Induced Peritonitis in Mice

et al. 2018

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Acute inflammation is a protective response of the host to physical injury and invading infection. Timely treatment of acute inflammatory reactions is essential to prevent damage to organisms that can eventually lead to chronic inflammation. Forsythoside A (FTA), an active constituent of Forsythia suspensa, has been reported to have anti-inflammatory, antioxidant, and antibacterial properties. Despite increasing knowledge of its anti-inflammatory effects, the mechanism and the effects on acute inflammation are poorly understood. This study is aimed at exploring the pro-resolving effects of FTA on zymosan-induced acute peritonitis. FTA significantly alleviated peritonitis as evidenced by the decreased number of neutrophils and levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) in the peritoneal cavity, without interfering with interleukin-10 (IL-10). FTA showed marked regulation of inflammatory cytokines and chemokine levels in zymosan-stimulated RAW 264.7 macrophages. Moreover, FTA could suppress the activation of NF-κB. In conclusion, FTA alleviated zymosan-induced acute peritonitis through inhibition of NF-κB activation.

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“…44 Moreover, in vitro experiments revealed that formation of p-bodies is critical to suppress inflammatory cytokine expression in endotoxin tolerant macrophages. 45 When we genetically removed p-bodies in hCT-MSCs by deleting DDX6 via Crispr/Cas9, DDX6-KO hCT-MSCs failed to reprogram monocytes and macrophages and suppress T H cells in vitro ( Figure 5D-G). in vivo data using an LPS-induced lung inflammation model demonstrated that DDX-KO hCT-MSC lost their ability to suppress inflammation and decrease the surface expression of MHC class II on infiltrating monocytes and macrophages that engulfed MSCs ( Figure 6C).…”

Section: Although Efferocytosis Likely Contributes To Engulfing and Cmentioning

confidence: 99%

Mesenchymal stromal cells reprogram monocytes and macrophages with processing bodies

Min

Parrott

et al. 2020

Stem Cells

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Mesenchymal stromal cells (MSCs) are widely used in clinical trials because of their ability to modulate inflammation. The success of MSCs has been variable over 25 years, most likely due to an incomplete understanding of their mechanism. After MSCs are injected, they traffic to the lungs and other tissues where they are rapidly cleared. Despite being cleared, MSCs suppress the inflammatory response in the long term. Using human cord tissue-derived MSCs (hCT-MSCs), we demonstrated that hCT-MSCs directly interact and reprogram monocytes and macrophages. After engaging hCT-MSCs, monocytes and macrophages engulfed cytoplasmic components of live hCT-MSCs, then downregulated gene programs for antigen presentation and costimulation, and functionally suppressed the activation of helper T cells. We determined that low-density lipoprotein receptor-related proteins on monocytes and macrophages mediated the engulfment of hCT-MSCs. Since a large amount of cellular information can be packaged in cytoplasmic RNA processing bodies (p-bodies), we generated p-body deficient hCT-MSCs and confirmed that they failed to reprogram monocytes and macrophages in vitro and in vivo. hCT-MSCs suppressed an inflammatory response caused by a nasal lipopolysaccharide challenge. Although both control and p-body deficient hCT-MSCs were engulfed by infiltrating lung monocytes and macrophages, p-body deficient hCT-MSCs failed to suppress inflammation and downregulate MHC-II. Overall, we identified a novel mechanism by which hCT-MSCs indirectly suppressed a T-cell response by directly interacting and reprogramming monocytes and macrophages via p-bodies. The results of this study suggest a novel mechanism for how MSCs can reprogram the inflammatory response and have long-term effects to suppress inflammation.

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Processing Body Formation Limits Proinflammatory Cytokine Synthesis in Endotoxin-Tolerant Monocytes and Murine Septic Macrophages

Cited by 10 publications

References 46 publications

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

Forsythoside A Modulates Zymosan-Induced Peritonitis in Mice

Mesenchymal stromal cells reprogram monocytes and macrophages with processing bodies

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