Identification of Adipose Tissue Dendritic Cells Correlated With Obesity-Associated Insulin-Resistance and Inducing Th17 Responses in Mice and Patients

Bertola, Adeline; Ciucci, Thomas; Rousseau, Denis; Bourlier, Virginie; Duffaut, Carine; Bonnafous, Stéphanie; Blin-Wakkach, Claudine; Anty, Rodolphe; Iannelli, Antonio; Gugenheim, Jean; Tran, Albert; Bouloumié, Anne; Gual, Philippe; Wakkach, Abdelilah

doi:10.2337/db11-1274

Cited by 329 publications

(326 citation statements)

References 41 publications

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“…These human data are consistent with work showing obesity-associated AT macrophages support inflammatory T-cell function in mice (36), although this study did not directly test the ability of macrophages from lean mice to support inflammatory T cells as did our work. Importantly, our human monocyte data significantly extend published data showing that dendritic cells promote Th17 function in obese mice (37). Although the monocyte-T-cell coculture data highlight disease-independent effects of monocytes on T cells, it remains possible that elevated monocyte cytokines in T2D (11) influence disease-associated T-cell function.…”

Section: Discussionsupporting

confidence: 70%

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

DeFuria

Belkina

Jagannathan-Bogdan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

449

442

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Patients with type 2 diabetes (T2D) have disease-associated changes in B-cell function, but the role these changes play in disease pathogenesis is not well established. Data herein show B cells from obese mice produce a proinflammatory cytokine profile compared with B cells from lean mice. Complementary in vivo studies show that obese B cell-null mice have decreased systemic inflammation, inflammatory B-and T-cell cytokines, adipose tissue inflammation, and insulin resistance (IR) compared with obese WT mice. Reduced inflammation in obese/insulin resistant B cell-null mice associates with an increased percentage of anti-inflammatory regulatory T cells (Tregs). This increase contrasts with the sharply decreased percentage of Tregs in obese compared with lean WT mice and suggests that B cells may be critical regulators of T-cell functions previously shown to play important roles in IR. We demonstrate that B cells from T2D (but not non-T2D) subjects support proinflammatory T-cell function in obesity/T2D through contact-dependent mechanisms. In contrast, human monocytes increase proinflammatory T-cell cytokines in both T2D and non-T2D analyses. These data support the conclusion that B cells are critical regulators of inflammation in T2D due to their direct ability to promote proinflammatory T-cell function and secrete a proinflammatory cytokine profile. Thus, B cells are potential therapeutic targets for T2D.immunometabolism | lymphocytes M ultiple studies support the concept that inflammation strongly associates with insulin resistance (IR), which, in addition to loss of islet function, defines type 2 diabetes (T2D) (1). Work implicating B cells in IR/T2D is limited. We showed B cells from T2D subjects secrete a proinflammatory cytokine profile, including an extraordinary inability to secrete the potent anti-inflammatory cytokine IL-10 and an elevated production of proinflammatory IL-8 compared with B cells from non-T2D subjects (2). Given the importance of B-cell IL-10 in preventing numerous inflammatory diseases (3, 4) and the links between IL-8 and T2D (5, 6), these data suggest that altered B-cell cytokine production plays an important role in initiating or promoting IR/T2D. Published analyses further support a role for B cells in IR and include studies of B cell-null New Zealand Obese (NZO) mice, which, in contrast to B cell-sufficient NZOs, fail to develop IR in response to obesity (7). These findings have been recently reproduced in studies showing obese B cell-null or B cell-depleted mice have less inflammation and IR than obese WT mice (8). Interestingly, T-cell cytokine production is decreased in obese B cell-null mouse adipose tissue (AT) (8), which raises the possibility that, in addition to production of a proinflammatory cytokine profile, B cells may function in IR by regulating the T cell-mediated inflammation known to drive disease pathogenesis (9, 10). We identified a proinflammatory T-cell ratio [defined by increased Th17 cells plus decreased regulatory T cells (Tregs)] in T2D patients that mirror...

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Section: Discussionsupporting

confidence: 70%

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

DeFuria

Belkina

Jagannathan-Bogdan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

449

442

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“…T cells infiltrate the AT in the early phase of DIO through chemokines, such as SDF1, which attract them to the AT (31 (33). The number of DCs positively correlates with BMI in men (33).…”

Section: T-cell Antigen-presenting Cell Interactions In Obesitymentioning

confidence: 99%

Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

et al. 2014

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In the past two decades, numerous experimental and clinical studies have established the importance of inflammation and immunity in the development of obesity and its metabolic complications, including insulin resistance and type 2 diabetes mellitus. In this context, T cells orchestrate inflammatory processes in metabolic organs, such as the adipose tissue (AT) and liver, thereby mediating obesity-related metabolic deterioration. Costimulatory molecules, which are present on antigen-presenting cells and naïve T cells in the AT, are known to mediate the crosstalk between the adaptive and innate immune system and to direct T-cell responses in inflammation. In this Perspectives in Diabetes article, we highlight the newest insights in immune cell interactions in obesity and discuss the role of costimulatory dyads in its pathogenesis. Moreover, the potential of therapeutic strategies that target costimulatory molecules in the metabolic syndrome is explored.

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“…A notable exception is the hormone adiponectin, with its anti-inflammatory and insulin sensitising actions (Ouchi et al, 1999;Yokota et al, 2000;Berg et al, 2001;Yamauchi et al, 2001), the production and secretion of which falls as fat mass expands (Arita et al, 1999;Hotta et al, 2000). The establishment of an inflammatory state in adipose tissue in obesity, which includes the recruitment of activated macrophages and other immune cells (Weisberg et al, 2003;Xu et al, 2003;Pond, 2005;Bertola et al, 2012;Brestoff et al, 2015), is widely considered to underpin the development of the diseases associated with the obese state.…”

Section: Introductionmentioning

confidence: 99%

PCR array and protein array studies demonstrate that IL-1β(interleukin-1β) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes

Alomar

Zaïbi

Kępczyńska

et al. 2015

Archives of Physiology and Biochemistry

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Identification of Adipose Tissue Dendritic Cells Correlated With Obesity-Associated Insulin-Resistance and Inducing Th17 Responses in Mice and Patients

Cited by 329 publications

References 41 publications

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

PCR array and protein array studies demonstrate that IL-1β(interleukin-1β) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes

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