Targeting Curcusomes to Inflammatory Dendritic Cells Inhibits NF-κB and Improves Insulin Resistance in Obese Mice

Yekollu, Suman; Thomas, Ranjeny; O’Sullivan, B.

doi:10.2337/db11-0275

Cited by 85 publications

(50 citation statements)

References 39 publications

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“…However, the role of other myeloid cells such as dendritic cells or granulocytes that are target cells of Cre-mediated gene deletion in Atg7 cKO mice 49 cannot be totally eliminated, as both granulocytes and dendritic cells participate in the insulin resistance associated with obesity. 50,51 The development of T2D in Atg7 cKO-ob/ob mice but not in lean Atg7 cKO mice suggests that autophagy-deficient myeloid cells do not display significant inflammatory phenotypes in the basal state, but show proinflammatory features in the presence of activators of inflammation or metabolic stress. Thus, autophagy-deficient Mfs appear to be susceptible to inflammasome activators such as lipids, which is the reason Atg7 cKO mice show increased inflammatory features and overt T2D when they become obese.…”

Section: Discussionmentioning

confidence: 99%

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

et al. 2016

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(2016) Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis, Autophagy, 12:8, 1390-1403, DOI: 10.1080/15548627.2016 ABSTRACT Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout [cKO] mice). While Atg7 cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to ob/w mice (Atg7 cKO-ob/ob mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. Mfs (macrophages) from Atg7 cKO mice showed significantly higher interleukin 1 b release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination. Moreover, a decrease in the NAD C :NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide were more pronounced in Mfs from Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient Mfs leads to an increase in lipid-induced inflammasome and metabolic deterioration in Atg7 cKO-ob/ob mice. Atg7 cKO mice were more susceptible to experimental colitis, accompanied by increased colonic cytokine expression, T helper 1 skewing and systemic bacterial invasion. These results suggest that autophagy of Mfs is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in Mfs may contribute to the progression of metabolic syndrome associated with lipid injury and colitis.

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Section: Discussionmentioning

confidence: 99%

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

et al. 2016

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“…Recent findings in monocytes from obese subjects, where insulin resistance is associated with increases in oxidative stress and activation of proinflammatory signaling molecules like c-Jun NH (2)-terminal kinase (JNK) and nuclear factor kB inhibitor kinase (IKK-b), indicate that the induction of stress kinase inhibitors such as heat-shock proteins (Hsp) 72 and Hsp27 improves insulin signaling via inhibition of stress kinases and the reduction of serine phosphorylated/inactivated IR substrate 1 (Simar et al 2012). Studies in obese mice have shown that targeting inflammatory dendritic cells improves insulin response resistance through NF-kB (Yekollu et al 2011). However, despite these promising observations, whether insulin resistance treatment or direct pharmacological targeting of inflammation suffices to completely restore the immune response in obese subjects and diabetic patients is still controversial.…”

Section: Insulin Resistance Immune Response Alterations and Cancer:mentioning

confidence: 99%

Insulin resistance and cancer: the role of insulin and IGFs

Djiogue¹,

Kamdje²,

Vecchio³

et al. 2012

Endocrine-Related Cancer

229

188

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Insulin, IGF1, and IGF2 are the most studied insulin-like peptides (ILPs). These are evolutionary conserved factors well known as key regulators of energy metabolism and growth, with crucial roles in insulin resistance-related metabolic disorders such as obesity, diseases like type 2 diabetes mellitus, as well as associated immune deregulations. A growing body of evidence suggests that insulin and IGF1 receptors mediate their effects on regulating cell proliferation, differentiation, apoptosis, glucose transport, and energy metabolism by signaling downstream through insulin receptor substrate molecules and thus play a pivotal role in cell fate determination. Despite the emerging evidence from epidemiological studies on the possible relationship between insulin resistance and cancer, our understanding on the cellular and molecular mechanisms that might account for this relationship remains incompletely understood. The involvement of IGFs in carcinogenesis is attributed to their role in linking high energy intake, increased cell proliferation, and suppression of apoptosis to cancer risks, which has been proposed as the key mechanism bridging insulin resistance and cancer. The present review summarizes and discusses evidence highlighting recent advances in our understanding on the role of ILPs as the link between insulin resistance and cancer and between immune deregulation and cancer in obesity, as well as those areas where there remains a paucity of data. It is anticipated that issues discussed in this paper will also recover new therapeutic targets that can assist in diagnostic screening and novel approaches to controlling tumor development.

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“…Curcumin liposomes reduced NF-κB and associated inflammatory cytokine production in TNF/iNOS liver dendritic cells and adipose tissue inflammatory macrophages (94).…”

Section: B Vitamin D3 As a Potential Therapeutic Agent For Nafld Trementioning

confidence: 97%

“…As it is highly lipophilic, curcumin bioavailability is also increased when complexed with liposomes, micelles and phospholipids (234). Curcumin liposomes have been shown to be beneficial in treating mice with insulin resistance (94). Curcumin liposomes delivered intraperitoneally to obese mice had reduced systemic insulin resistance as measured by homeostasis model assessment-estimated insulin resistance (HOMA-IR).…”

Section: B Vitamin D3 As a Potential Therapeutic Agent For Nafld Trementioning

confidence: 99%

“…Myeloid specific genetic ablation of NF-κB reduces insulin resistance in obese mice, nevertheless accomplishing this with pharmaceutical agents is challenging (74). We recently showed that this could be achieved through liposome nanoparticles entrapped with anti-inflammatory drug curcumin (curcumin liposomes) (94). Curcumin liposomes significantly reduced NF-κB nuclear translocation in targeted DCs.…”

Section: Targeting Liver Myeloid Cells With Curcumin Liposomes Inducementioning

confidence: 99%

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Targeting liver inflammatory myeloid cells with immunomodulatory liposomes improves nonalcoholic steatohepatitis in mice

Maradana¹

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Nonalcoholic steatohepatitis (NASH) is a major complication in patients with obesity and type 2 diabetes, and can progress to cirrhosis, liver failure and death. No effective treatments exist. NASH is characterized by steatosis and increased numbers of inflammatory myeloid cells in the liver, and depletion of myeloid cells with toxic-liposomes reduces disease. Liposomes therefore offer a means to selectively target myeloid cells with compounds that inhibit inflammatory pathways.In this thesis I investigate whether anti-inflammatory compounds, encapsulated into 100 nm liposomes can target inflammatory myeloid cells, inhibit inflammatory pathways in myeloid cells and the outcome of this on liver disease. Two rodent NASH models were examined:an acute model where mice were fed methionine and choline deficient (MCD) diet for 3 weeks and a chronic model where mice were fed a high-fat high-sugar (HFHS) diet for 14 weeks.In the acute MCD model, mice developed severe steatohepatitis, with increased proportions Together these data indicate that anti-inflammatory drugs including curcumin and vitamin D3, encapsulated in liposomes, target hepatic inflammatory DCs, induce alternative/tolerogenic phenotype and prevent steatohepatitis progression to liver fibrosis.Curcumin liposomes coupled with ovalbumin, co-injected with ovalbumin-specific regulatory T cells has an additional therapeutic effect. These findings demonstrate the importance of both innate and adaptive immune cells in progression of liver disease and the feasibility of delivering anti-inflammatory drugs and antigen to these cells to treat NASH.

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Targeting Curcusomes to Inflammatory Dendritic Cells Inhibits NF-κB and Improves Insulin Resistance in Obese Mice

Cited by 85 publications

References 39 publications

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

Insulin resistance and cancer: the role of insulin and IGFs

Targeting liver inflammatory myeloid cells with immunomodulatory liposomes improves nonalcoholic steatohepatitis in mice

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