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 (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.

REDD‐1 aggravates endotoxin‐induced inflammationVIAatypical NF‐κB activation

“…Parthenolide, an IKK inhibitor (28), led to an increase of delayed NF-kB activation and cytokine gene expression (6-12 h) in LPS-challenged mice, although it inhibited early NF-kB-dependent cytokine gene expression (1-3 h) (27), suggesting that NF-kB is activated by 2 distinct mechanisms, such as the early IKK-dependent and the delayed IKK-independent pathways. Our data also indicate that delayed NF-kB activation is linked to the induction of REDD-1 in LPS-stimulated macrophages and endotoxemic mice, suggesting that REDD-1 acts as a positive modulator of the immune response (25). Thus, REDD-1 stimulates atypical NF-kB activation independently of the classic pathway.…”

“…Therefore, knockdown or heterozygous deletion of REDD-1 protected mice from endotoxemic lung and liver injury, as well as lethality. REDD-1 is up-regulated by several stimuli, including hypoxia, reactive oxygen species, and LPS (8)(9)(10)(11)(12)25). Data from our earlier study demonstrated that LPS strongly induces REDD-1 expression in cultured macrophages via cAMP response element-binding protein-dependent signal mechanism (10), suggesting the possibility that LPS-induced REDD-1 plays a role in regulating the inflammatory response.…”

“…Thus, REDD-1 stimulates atypical NF-kB activation independently of the classic pathway. Some studies have revealed the possible involvement of REDD-1 in NF-kB activation and inflammation in mice exposed to LPS or cigarette smoke; however, the inflammatory processes were markedly abrogated in REDD-1 2/2 mice (11,12,25). REDD-1 is a known endogenous inhibitor of mTORC-1 through activation of tumor suppressor complex-2 (9); therefore, it is possible that REDD-1 stimulates the NF-kB-dependent inflammatory response through the inhibition of mTOR activity.…”

“…inflammatory response has been also reported between WT and REDD-1 2/2 mice exposed to LPS or cigarette smoke (11,12). However, a recent study demonstrated that rapamycin neither alters LPS-induced NF-kB activation in normal macrophages nor restores decreased NF-kB p65 phosphorylation in LPS-stimulated REDD-1 2/2 macrophages (25). Similarly, our data clearly showed that mTOR inhibition did not affect REDD-1-mediated NF-kB activation, suggesting that the proinflammatory activity of REDD-1 is not directly mediated by mTOR inhibition.…”

REDD1/Autophagy Pathway Is Associated with Neutrophil-Driven IL-1β Inflammatory Response in Active Ulcerative Colitis

“…DDIT4/REDD1 protein (hereinafter referred to as REDD1) is an important component of energy homeostasis implicated in the activation of several inflammatory pathways (16,17). It is upregulated by various stressors, such as glucocorticoids, adrenaline, DNA damage, and hypoxia, and has been correlated with the regulation of autophagy through mTOR or oxidative stress (12,18,19).…”