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Macrophage expression of E3 ubiquitin ligase Grail protects mice from lipopolysaccharide-induced hyperinflammation and organ injury.
- Source :
-
PloS one [PLoS One] 2018 Dec 20; Vol. 13 (12), pp. e0208279. Date of Electronic Publication: 2018 Dec 20 (Print Publication: 2018). - Publication Year :
- 2018
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Abstract
- Multiple organ dysfunction caused by hyperinflammation remains the major cause of mortality during sepsis. Excessive M1-macrophage activation leads to systemic inflammatory responses. Gene related to anergy in lymphocytes (Grail) is regarded as an important regulator of T cells that functions by diminishing cytokine production. However, its role in regulating macrophage activation and organ injury during sepsis remains unclear. Our aim was to examine the effects of Grail on macrophage reactivity and organ injury in endotoxemic animals. Wild-type and Grail knockout mice were injected with vehicle or Escherichia coli lipopolysaccharide and observed for 24 h. Changes in blood pressure, heart rate, blood glucose, and biochemical variables were then examined. Moreover, levels of neutrophil infiltration, MMP-9, and caspase 3 were analyzed in the lungs of animals. The expression of pro-inflammatory cytokines in J774A, RAW264.7, and primary peritoneal macrophages stimulated with LPS were also assessed in the presence or absence of Grail. Results indicated that loss of Grail expression enhances the induction of pro-inflammatory cytokines in J774A, RAW264.7, and primary peritoneal macrophages treated with LPS. Furthermore, LPS-induced macrophage hyperactivation was alleviated by ectopic Grail overexpression. In vivo studies showed that Grail deficiency exacerbates organ damage in endotoxemic animals. Levels of neutrophil infiltration, MMP-9, and caspase 3 were significantly increased in the lungs of Grail-deficient endotoxemic mice. Thus, these results suggest that Grail contributes to the attenuation of hyperinflammation caused by activated macrophages and prevents organ damage in endotoxemic mice. We suggest that Grail signaling could be a therapeutic target for endotoxemia.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Animals
Body Weight
Caspase 3 metabolism
Creatinine blood
Cytokines metabolism
Endotoxemia blood
Endotoxemia metabolism
Endotoxemia pathology
Gene Deletion
Hemodynamics
Inflammation pathology
Inflammation Mediators metabolism
L-Lactate Dehydrogenase blood
Lipopolysaccharides
Lung enzymology
Lung pathology
Male
Matrix Metalloproteinase 9 metabolism
Mice
Mice, Inbred C57BL
Neutrophil Infiltration
RAW 264.7 Cells
Inflammation enzymology
Inflammation prevention & control
Macrophages, Peritoneal enzymology
Organ Specificity
Ubiquitin-Protein Ligases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 13
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 30571701
- Full Text :
- https://doi.org/10.1371/journal.pone.0208279