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 (TNFα, IL-6, IL-1β) 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-κB and NLRP3 inflammasome leading to a reduction of IL-1β 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.
Highlights
Inflammation is the response of the innate immune system to pathogens or injury and is due to secretion of proinflammatory cytokines
We demonstrate that loss of REDD1 inhibited the activation of p38 MAPK, JNK and NF-κB in response to LPS stimulation, as well as the activation of NLRP3 inflammasome and IL1β production in bone marrow derived macrophages or in adipose tissue explants from REDD1−/− mice
Since REDD1 has been implicated in the activation of proinflammatory pathways in epithelial cells, we evaluated the effect of knockout of REDD1 on LPS-induced cytokines expression in adipose tissue
Summary
Inflammation is the response of the innate immune system to pathogens or injury and is due to secretion of proinflammatory cytokines. Increased LPS-induced endotoxemia activates TLR4 and downstream pathways such as MAP kinases and NF-κB signaling pathways to promote proinflammatory cytokine secretion, such as IL-1β. LPS injection in mice leads to an increase expression and secretion of proinflammatory cytokines including TNFα, IL-1β and IL-6. These proinflammatory cytokines are produced by cells from the stromal vascular fraction such as macrophages, rather than adipocytes[3, 4]. Insulin stimulates REDD1 expression by inhibiting its degradation through a MEK-dependent pathway[12] and by activating its transcriptional regulation by HIF-1 transcription factor[13]. REDD1 participates to glucocorticoid signaling and loss of REDD1 protects mice from muscle atrophy induced by dexamethasone[20]
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