Éditeur(s) : HAL CCSD
Résumé : International audience
The development of diabetic vascular complications is initiated, at least in part, by mitochondrial reactive oxygen species (ROS) production in endothelial cells. Hyperglycemia induces superoxide production in the mitochondria and initiates changes in the mitochondrial membrane potential that leads to mitochondrial dysfunction. Hydrogen sulfide (H2S) supplementation has been shown to reduce the mitochondrial oxidant production and shows efficacy against diabetic vascular damage in vivo. However, the half-life of H2S is very short and it is not specific for the mitochondria. We have therefore evaluated two novel mitochondria-targeted anethole dithiolethione and hydroxythiobenzamide H2S donors (AP39 and AP123 respectively) at preventing hyperglycemia-induced oxidative stress and metabolic changes in microvascular endothelial cells in vitro. Hyperglycemia (HG) induced significant increase in the activity of the citric acid cycle and led to elevated mitochondrial membrane potential. Mitochondrial oxidant production was increased and the mitochondrial electron transport decreased in hyperglycemic cells. AP39 and AP123 (30–300 nM) decreased HG-induced hyperpolarisation of the mitochondrial membrane and inhibited the mitochondrial oxidant production. Both H2S donors (30–300 nM) increased the electron transport at respiratory complex III and improved the cellular metabolism. Targeting H2S to mitochondria retained the cytoprotective effect of H2S against glucose-induced damage in endothelial cells suggesting that the molecular target of H2S action is within the mitochondria. Mitochondrial targeting of H2S also induced >1000-fold increase in the potency of H2S against hyperglycemia-induced injury. The high potency and long-lasting effect elicited by these H2S donors strongly suggests that these compounds could be useful against diabetic vascular complications. © 2016
Pharmacological Research

hal-01373947
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01373947
DOI : 10.1016/j.phrs.2016.08.019
PUBMED : 27565382

Éditeur(s) : HAL CCSD Federation of American Society of Experimental Biology
Résumé : International audience
The innate immune system is able to detect bacterial LPS through the pattern recognition receptor CD14, which delivers LPS to various TLR signaling complexes that subsequently induce intracellular proinflammatory signaling cascades. In a previous study, we showed the overproduction of the soluble form of CD14 (sCD14) by macrophages from patients with cystic fibrosis (CF). CF is an autosomal recessive disorder that is caused by mutations in the gene that encodes the CFTR protein and is characterized by persistent inflammation. Macrophages play a significant role in the initial stages of this disease due to their inability to act as suppressor cells, leading to chronic inflammation in CF. In this work, we investigated the origin of sCD14 by human macrophages and studied the effect of sCD14 on the production of inflammatory cytokine/chemokine. Our data indicate that sCD14 stimulate proinflammatory cytokine/chemokine production in a manner that is independent of LPS but dependent on the TLR-4/CD14 membrane complex, NF-κB, and the inflammasome. Therefore, sCD14, overproduced by CF macrophages, originates primarily from the endocytosis/exocytosis process and should be considered to be a danger-associated molecular pattern. This elucidation of the origin and inflammation-induced mechanisms associated with sCD14 contributes to our understanding of maintained tissue inflammation.
ISSN: 0892-6638

hal-01526434
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526434
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526434/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526434/file/Soluble%20CD14%20acts%20as%20a%20DAMP%20in%20human-accepted.pdf
PUBMED : 28122919

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The underlying cause of morbidity in cystic fibrosis (CF) is the decline in lung function, which results in part from chronic inflammation. Inflammation and infection occur early in infancy in CF and the role of innate immune defense in CF has been highlighted in the last years. Once thought simply to be consumers of bacteria, macrophages have emerged as highly sensitive immune cells that are located at the balance point between inflammation and resolution of this inflammation in CF pathophysiology. In order to assess the potential role of macrophage in CF, we review the evidence that: (1) CF macrophage has a dysregulated inflammatory phenotype; (2) CF macrophage presents altered phagocytosis capacity and bacterial killing; and (3) lipid disorders in CF macrophage affect its function. These alterations of macrophage weaken innate defense of CF patients and may be involved in CF disease progression and lung damage.
ISSN: 1569-1993

hal-01560280
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560280/file/Chouly-The%20impact%20of%20impaired%20macrophage%20functions.pdf
DOI : 10.1016/j.jcf.2016.10.011