Immune Regulation in Obesity-Associated Adipose Inflammation

Han, Jonathan M.; Levings, Megan K.

doi:10.4049/jimmunol.1301035

Cited by 133 publications

(110 citation statements)

References 63 publications

(84 reference statements)

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“…Visceral AT contains a wide array of immune cells (7), and in lean individuals, resident immune cells are typically associated with a type 2 immune axis, including M2 macrophages, eosinophils, invariant natural killer T (iNKT) cells, group 2 innate lymphoid cells (ILC2s), T-helper type 2 (Th2) cells, and regulatory T (Treg) cells (Figure 1). The conclusion that type 2 cytokines have an essential role in maintaining a normal balance of white and beige AT, as well as metabolism, comes from evidence that mice lacking interleukin (IL)-4 and IL-13 have reduced UCP1 Figure 1: Immune regulation in lean versus obese adipose tissue (AT).…”

Section: Immune Cell Composition In Lean Atmentioning

confidence: 99%

Obesity-Associated Adipose Tissue Inflammation and Transplantation

Wu¹,

Dawson²,

Levings³

2016

American Journal of Transplantation

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Obesity is often associated with the development of adipose tissue (AT) inflammation, resulting in metabolic dysfunction and an increased risk for developing type 2 diabetes. It is also associated with multiple chronic diseases, including cardiovascular, liver, and kidney disease, and thus can contribute to organ failure. Several studies have investigated whether there is a correlation between obesity and outcomes in transplantation, but there is currently very limited information on the specific role of AT inflammation in the rejection process or on the overall function of the transplanted organ. Here, we provide a brief review of the current understanding of the cellular mechanisms that control obesity-associated AT inflammation and summarize knowledge about how obesity affects clinical outcomes following solid organ or hematopoietic stem cell transplantation. We also highlight opportunities for more research to better understand how obesity affects outcomes of transplantation.

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Section: Immune Cell Composition In Lean Atmentioning

confidence: 99%

Obesity-Associated Adipose Tissue Inflammation and Transplantation

Wu¹,

Dawson²,

Levings³

2016

American Journal of Transplantation

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“…Macrophage accumulation is mediated by recruitment of blood monocytes as well as by in situ proliferation of resident macrophages (5,6). Additionally, the phenotype of ATM 3 subpopulations shifts from a non-inflammatory phenotype toward a pro-inflammatory phenotype characterized by the production of pro-inflammatory cytokines, which impair adipocyte function and promote insulin resistance (7,8).…”

mentioning

confidence: 99%

“…Its development is attributed to the accumulation of macrophages and other immune cell types and the overproduction of pro-inflammatory cytokines (3,4). Macrophage accumulation is mediated by recruitment of blood monocytes as well as by in situ proliferation of resident macrophages (5,6).…”

mentioning

confidence: 99%

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Snodgrass¹,

Boß²,

Zezina³

et al. 2016

Journal of Biological Chemistry

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Pro-inflammatory cytokines secreted by adipose tissue macrophages (ATMs) contribute to chronic low-grade inflammation and obesity-induced insulin resistance. Recent studies have shown that adipose tissue hypoxia promotes an inflammatory phenotype in ATMs. However, our understanding of how hypoxia modulates the response of ATMs to free fatty acids within obese adipose tissue is limited. We examined the effects of hypoxia (1% O 2 ) on the pro-inflammatory responses of human monocyte-derived macrophages to the saturated fatty acid palmitate. Compared with normoxia, hypoxia significantly increased palmitate-induced mRNA expression and protein secretion of IL-6 and IL-1␤. Although palmitate-induced endoplasmic reticulum stress and nuclear factor B pathway activation were not enhanced by hypoxia, hypoxia increased the activation of JNK and p38 mitogen-activated protein kinase signaling in palmitate-treated cells. Inhibition of JNK blocked the hypoxic induction of pro-inflammatory cytokine expression, whereas knockdown of hypoxia-induced transcription factors HIF-1␣ and HIF-2␣ alone or in combination failed to reduce IL-6 and only modestly reduced IL-1␤ gene expression in palmitate-treated hypoxic macrophages. Enhanced pro-inflammatory cytokine production and JNK activity under hypoxia were prevented by inhibiting reactive oxygen species generation. In addition, silencing of dual-specificity phosphatase 16 increased normoxic levels of IL-6 and IL-1␤ and reduced the hypoxic potentiation in palmitate-treated macrophages. The secretome of hypoxic palmitate-treated macrophages promoted IL-6 and macrophage chemoattractant protein 1 expression in primary human adipocytes, which was sensitive to macrophage JNK inhibition. Our results reveal that the coexistence of hypoxia along with free fatty acids exacerbates macrophage-mediated inflammation.

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“…Obesity-associated chronic inflammation is a complex phenomenon that results from the interaction between adipose tissue, hyperinsulinemia, and chronic inflammation [1][2][3][4]. Together, these linked conditions increase the risk to develop metabolic syndrome and type-2 diabetes mellitus.…”

Section: Introductionmentioning

confidence: 99%

“…These probably play important roles in the onset of inflammatory responses, and their systemic impact remains unresolved. A starting point, involves understanding: (i) the complex regulatory network involved in the cell fate attainment of CD4+ T cell types [11][12][13], (ii) how such network responds to extracellular metabolic and microenvironmental conditions [14,15], and (iii) how the resulting system dynamically modulates the inflammatory and immune responses [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

The CD4+ T cell regulatory network mediates inflammatory responses during acute hyperinsulinemia: a simulation study

Martinez-Sanchez

Hiriart

Álvarez-Buylla

2016

Preprint

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Background: Obesity is frequently linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behaviour of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood. Results: We model how hyperinsulinemia alters the dynamics of the CD4+ T regulatory network, and this, in turn, modulates cell differentiation and plasticity. Different polarizing microenvironments are simulated under basal and high levels of insulin to assess impacts on cell-fate attainment and robustness in response to transient perturbations. In the presence of high levels of insulin Th1 and Th17 become more stable to transient perturbations, and their basin sizes are augmented, Tr1 cells become less stable or disappear, while TGFβ producing cells remain unaltered. Hence, the model provides a dynamic system-level framework and explanation to further understand the documented and apparently paradoxical role of TGFβ in both inflammation and regulation of immune responses, as well as the emergence of the adipose Treg phenotype. Furthermore, our simulations provide new predictions on the impact of the microenvironment in the coexistence of the different cell types, suggesting that in pro-Th1, pro-Th2 and pro-Th17 environments effector and regulatory cells can coexist, but that high levels of insulin severely diminish regulatory cells, especially in a pro-Th17 environment. Conclusions: This work provides a first step towards a system-level formal and dynamic framework to integrate further experimental data in the study of complex inflammatory diseases.

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Immune Regulation in Obesity-Associated Adipose Inflammation

Cited by 133 publications

References 63 publications

Obesity-Associated Adipose Tissue Inflammation and Transplantation

Obesity-Associated Adipose Tissue Inflammation and Transplantation

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

The CD4+ T cell regulatory network mediates inflammatory responses during acute hyperinsulinemia: a simulation study

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