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Implication of REDD1 in the activation of inflammatory pathways.

ABSTRACT: In response to endotoxemia, the organism triggers an inflammatory response, and the visceral adipose tissue represents a major source of proinflammatory cytokines. The regulation of inflammation response in the adipose tissue is thus of crucial importance. We demonstrated that Regulated in development and DNA damage response-1 (REDD1) is involved in inflammation. REDD1 expression was increased in response to lipopolysaccharide (LPS) in bone marrow derived macrophages (BMDM) and in epidydimal adipose tissue. Loss of REDD1 protected the development of inflammation, since the expression of proinflammatory cytokines (TNF?, IL-6, IL-1?) was decreased in adipose tissue of REDD1^-/- mice injected with LPS compared to wild-type mice. This decrease was associated with an inhibition of the activation of p38MAPK, JNK, NF-?B and NLRP3 inflammasome leading to a reduction of IL-1? secretion in response to LPS and ATP in REDD1^-/- BMDM. Although REDD1 is an inhibitor of mTORC1, loss of REDD1 decreased inflammation independently of mTORC1 activation but more likely through oxidative stress regulation. Absence of REDD1 decreases ROS associated with a dysregulation of Nox-1 and GPx3 expression. Absence of REDD1 in macrophages decreases the development of insulin resistance in adipocyte-macrophage coculture. Altogether, REDD1 appears to be a key player in the control of inflammation.

SUBMITTER: Pastor F

PROVIDER: S-EPMC5539207 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Implication of REDD1 in the activation of inflammatory pathways.

Pastor Faustine F Dumas Karine K Barthélémy Marie-Astrid MA Regazzetti Claire C Druelle Noémie N Peraldi Pascal P Cormont Mireille M Tanti Jean-François JF Giorgetti-Peraldi Sophie S

Scientific reports 20170801 1

In response to endotoxemia, the organism triggers an inflammatory response, and the visceral adipose tissue represents a major source of proinflammatory cytokines. The regulation of inflammation response in the adipose tissue is thus of crucial importance. We demonstrated that Regulated in development and DNA damage response-1 (REDD1) is involved in inflammation. REDD1 expression was increased in response to lipopolysaccharide (LPS) in bone marrow derived macrophages (BMDM) and in epidydimal adi ...[more]

PMID: 28765650

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Project description:Stress cardiomyopathy (SCM) is a unique cardiac disorder that more often occurs in women. SCM presents in a similar fashion as acute myocardial infarction (AMI), with chest pain, ECG changes, and congestive heart failure. The primary distinguishing feature is the absence of thrombotic coronary occlusion in SCM. How this reduction in cardiac function occurs in the absence of coronary occlusion remains unknown. Therefore, we tested the hypothesis that a targeted proteomic comparison of patients with acute SCM and AMI might identify relevant mechanistic differences. Blood was drawn in normal controls (n?=?6), women with AMI (n?=?12), or women with acute SCM (n?=?15). Two-week follow-up samples were available in AMI (n?=?4) and SCM patients (n?=?11). Relative concentrations of 1,310 serum proteins were measured in each of the 48 samples using the SOMAscan assay. Women with AMI had greater myocyte necrosis, as reflected by a higher peak troponin I concentration (AMI 32.03?±?29.46 vs. SCM 2.68?±?2.6?ng/ml, p?<?0.05). AMI and SCM patients had equivalent reductions in left ventricular ejection fraction [LVEF (%) 39?±?12 vs. 37?±?12, p?=?0.479]. In follow-up, women with SCM had a greater improvement in cardiac function [LVEF (%) 60?±?7 vs. 45?±?13, p?<?0.001]. No differentially expressed proteins were detected (absolute log2-fold change >1; q?<?0.05) between AMI and SCM in the acute or recovery phase. However, when we compared normal controls to patients with AMI, there was differential expression of 35 proteins. When we compared normal controls to patients with SCM, 45 proteins were differentially expressed. In comparison to normal controls, biological processes such as complement, coagulation, and inflammation were activated in both AMI and SCM. There were four proteins that showed a non-significant trend to be increased in acute SCM vs. AMI (netrin-1, follistatin-like 3, kallikrein 7, kynureninase). Despite a lesser degree of myocardial necrosis than AMI, SCM is characterized by a similar activation of inflammatory, complement, and coagulation pathways. These findings may explain reported thromboembolic complications in the short term and elevated risk of mortality in the long term of SCM.

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Implication of REDD1 in the activation of inflammatory pathways.

Publications

Implication of REDD1 in the activation of inflammatory pathways.

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