BZ-26, a novel GW9662 derivate, attenuated inflammation by inhibiting the differentiation and activation of inflammatory macrophages

Bei, Yuncheng; Chen, Jiajia; Zhou, Feifei; Huang, Yue; Jiang, Nan; Tan, Renxiang; Shen, Pingping

doi:10.1016/j.biopha.2016.08.069

Cited by 7 publications

(9 citation statements)

References 31 publications

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“…Surprisingly, we found that PPARγ antagonism reduced EAE disease severity compared to that in the control mice. The latter finding contradicts the beneficial impact of PPARγ agonists in the EAE model but is consistent with GW9662 displaying anti-inflammatory properties in vitro and in vivo [48]. Overall, our findings identify the SCD1-ATGL-PPAR axis as a key signaling pathway in driving Treg differentiation and highlight the complexity of PPAR signaling in (auto)immune disorders.…”

Section: Discussionsupporting

confidence: 69%

“…6F ). The latter finding contradicts the protective impact of PPARγ agonists in the EAE model [ 47 ] but is consistent with GW9662 displaying anti-inflammatory properties in in vitro immune cell cultures and an LPS-triggered acute inflammation mouse model [ 48 ]. Consistent with changes in EAE disease severity, Scd1 −/−- induced changes in CNS inflammation, accumulation of CD3 + T cells, and demyelination were no longer apparent in the presence of GW9662 (Supplementary Fig.…”

Section: Resultssupporting

confidence: 55%

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Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

et al. 2023

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The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.

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Section: Discussionsupporting

confidence: 69%

Section: Resultssupporting

confidence: 55%

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

et al. 2023

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“…Surprisingly, we find that PPARγ antagonism reduces EAE disease severity as compared to control mice. The latter finding contradicts with the beneficial impact of PPARγ agonists in the EAE model but is consistent with GW9662 displaying anti-inflammatory properties in vitro and in vivo (31). All in all, our findings identify the SCD1-ATGL-PPAR axis as a key signaling pathway in driving Treg differentiation and highlight the complexity of PPAR signaling in (auto)immune disorders.…”

Section: Discussionmentioning

confidence: 59%

“…Surprisingly, PPARγ antagonism reduced EAE disease severity as compared to control mice (Figure 6G). The latter finding contradicts with the protective impact of PPARγ agonists in the EAE model (30), but is consistent with GW9662 displaying antiinflammatory properties in in vitro immune cell cultures and an LPS-triggered acute inflammation mouse model (31). In line with changes in EAE disease severity, Scd1 -/induced changes in CNS inflammation and accumulation of CD3 + T cells were no longer apparent in the presence of GW9662 (Supplemental Figure 8, E-G).…”

Section: Non-esterified Dha Promotes Treg Differentiation Through Pparγmentioning

confidence: 63%

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

Grajchen

Loix

Baeten

et al. 2022

Preprint

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The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T cell (Treg) differentiation and augments autoimmunity in an animal model of MS. Guided by RNA sequencing and lipidomics analysis, we found that absence of Scd1 promotes hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders.

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“…It has shown that among the novel small molecules derived from GW9662, BZ-26 has a stronger interaction with PPAR-γ and higher transcriptional inhibitory activity of PPAR-γ compared with GW9662. BZ-26 inhibits inflammatory macrophage differentiation of THP1 human monocytic cell line (Bei et al, 2016). Moreover, BZ-26 attenuates the inflammatory responses in LPS-triggered acute inflammation mouse model down-regulating peripheral TNF-α and IL-6 level.…”

Section: Nuclear Receptors As Macrophage Therapeutic Targetmentioning

confidence: 99%

Role of Myeloid-Epithelial-Reproductive Tyrosine Kinase and Macrophage Polarization in the Progression of Atherosclerotic Lesions Associated With Nonalcoholic Fatty Liver Disease

et al. 2019

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Recent lines of evidence highlight the involvement of myeloid-epithelial-reproductive tyrosine kinase (MerTK) in metabolic disease associated with liver damage. MerTK is mainly expressed in anti-inflammatory M2 macrophages where it mediates transcriptional changes including suppression of proinflammatory cytokines and enhancement of inflammatory repressors. MerTK is regulated by metabolic pathways through nuclear sensors including LXRs, PPARs, and RXRs, in response to apoptotic bodies or to other sources of cholesterol. Nonalcoholic fatty liver disease (NAFLD) is one of the most serious public health problems worldwide. It is a clinicopathological syndrome closely related to obesity, insulin resistance, and oxidative stress. It includes a spectrum of conditions ranging from simple steatosis, characterized by hepatic fat accumulation with or without inflammation, to nonalcoholic steatohepatitis (NASH), defined by hepatic fat deposition with hepatocellular damage, inflammation, and accumulating fibrosis. Several studies support an association between NAFLD and the incidence of cardiovascular diseases including atherosclerosis, a major cause of death worldwide. This pathological condition consists in a chronic and progressive inflammatory process in the intimal layer of large- and medium-sized arteries. The complications of advanced atherosclerosis include chronic or acute ischemic damage in the tissue perfused by the affected artery, leading to cellular death. By identifying specific targets influencing lipid metabolism and cardiovascular-related diseases, the present review highlights the role of MerTK in NAFLD-associated atherosclerotic lesions as a potential innovative therapeutic target. Therapeutic advantages might derive from the use of compounds selective for nuclear receptors targeting PPARs rather than LXRs regulating macrophage lipid metabolism and macrophage mediated inflammation, by favoring the expression of MerTK, which mediates an immunoregulatory action with a reduction in inflammation and in atherosclerosis.

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BZ-26, a novel GW9662 derivate, attenuated inflammation by inhibiting the differentiation and activation of inflammatory macrophages

Cited by 7 publications

References 31 publications

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

Role of Myeloid-Epithelial-Reproductive Tyrosine Kinase and Macrophage Polarization in the Progression of Atherosclerotic Lesions Associated With Nonalcoholic Fatty Liver Disease

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