A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity

Chung, Kyoung‐Jin; Chatzigeorgiou, Antonios; Economopoulou, Matina; García‐Martín, Rubén; Alexaki, Vasileia Ismini; Mitroulis, Ioannis; Nati, Marina; Gebler, Janine; Ziemssen, Tjalf; Goelz, Susan; Phieler, Julia; Lim, Jin Ho; Karalis, Katia; Papayannopoulou, Thalia; Blüher, Matthias; Hajishengallis, George; Chavakis, Triantafyllos

doi:10.1038/ni.3728

Cited by 145 publications

(145 citation statements)

References 65 publications

(117 reference statements)

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“…Alternatively activated macrophages have been proposed to promote adaptive thermogenesis directly via their production of catecholamines (Nguyen et al, 2011), although independent studies found that adipose tissue macrophages from cold-exposed mice do not express the key catecholamine synthesis enzyme tyrosine hydroxylase (TH) (Chang et al, 2016; Fischer et al, 2017; Spadaro et al, 2017), and TH deletion in hematopoietic cells neither affected adipose tissue browning nor energy expenditure in response to cold (Fischer et al, 2017). In contrast, polarization towards a more proinflammatory activation directly inhibits adipose tissue browning (Chung et al, 2017) and in turn, browning has been described to limit adipose tissue inflammation (Cohen et al, 2014). However, regardless of whether macrophages directly promote thermogenesis, all of these studies confirm the presence of immune cells resident in adipose tissue in homeostatic and adaptive settings.…”

Section: Innate Immune Cellular Mediators Of Inflammationmentioning

confidence: 99%

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

2017

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Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health.

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Section: Innate Immune Cellular Mediators Of Inflammationmentioning

confidence: 99%

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

2017

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“…Adhesion was performed as previously described with modifications (29,76,77). Nunc-Immuno MicroWell 96-well solid plates (Sigma-Aldrich) were coated overnight at 4°C with Del-1-Fc (10 μg/ml) and washed twice with PBS, and blockade was performed with 1% BSA in PBS for 1 hour.…”

Section: Cell Cycle Analysis Of Lt-hscs From Edil3mentioning

confidence: 99%

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Mitroulis¹,

Chen²,

Singh³

et al. 2017

Journal of Clinical Investigation

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es. We show that Del-1, via its interaction with the αvβ3 integrin, promotes several critical functions in the niche, including HSC retention, hematopoietic progenitor cell cycle progression, and myeloid lineage commitment of HSCs. Del-1 thereby regulates myelopoiesis under steady-state conditions and in G-CSF-or inflammation-induced stress myelopoiesis, as well as myelopoiesis reconstitution under regenerative/transplantation conditions. Del-1 is hence a niche component that serves a juxtacrine homeostatic adaptation of the hematopoietic system in inflammation-related and regeneration myelopoiesis. ResultsDel-1 expression in the BM. First, we sought to investigate whether Del-1 is present in the BM. We initially studied the expression of the Del-1-encoding gene Edil3 in the BM niche and hematopoietic cell populations. We found that Edil3 mRNA expression was significantly higher in the endosteal region as compared with the central BM (cBM) ( Figure 1A), suggesting that Del-1 is enriched at the endosteal area of the BM. Analysis of sorted cells from CXCL12-GFP mice (33, 34) demonstrated that Edil3 was highly expressed integrin receptors (29-31). It consists of three N-terminal EGF-like repeats and two C-terminal discoidin I-like domains, and hence also is designated EGF-like repeats and discoidin-I-like domains-3 (EDIL3) (32). We have previously identified Del-1 as an endogenous modulator of leukocyte adhesion through interaction with integrin αLβ2 (LFA-1; CD11a/CD18) (29, 31). Moreover, Del-1 interacts with β3 integrin (CD61) via an Arg-Gly-Asp (RGD) motif on the second EGF-like repeat (30).In the present work, we observed that Del-1 is expressed by several major cellular components of the HSC niche, though not by hematopoietic progenitors. In particular, Del-1 is expressed by those niche cells that have a major role in the maintenance of HSCs, i.e., arteriolar endothelial cells and perivascular CAR cells (3,6,7,9,15). In addition, Del-1 is expressed by cells of the osteoblastic lineage that crucially mediate the engraftment of HSCs in the post-transplantation niche (3,17,18). This spatial distribution of Del-1 raised the possibility that it might be involved in the regulation of hematopoiesis. We addressed this hypothesis using in vivo models of steady-state, regenerative, and stress hematopoiesis and in vitro mechanistic approach-

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“…Microglia cells were isolated from Hif2a-HWT and Hif2a-HKO mice according to previously described protocols (27,28). Bone marrow-derived macrophages (BMDM) were isolated according to previously described protocols (29,30).…”

Section: Cell Culturementioning

confidence: 99%

Hematopoietic hypoxia‐inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis

et al. 2018

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A hallmark of proliferative retinopathies, such as retinopathy of prematurity (ROP), is a pathological neovascularization orchestrated by hypoxia and the resulting hypoxia-inducible factor (HIF)-dependent response. We studied the role of Hif2α in hematopoietic cells for pathological retina neovascularization in the murine model of ROP, the oxygen-induced retinopathy (OIR) model. Hematopoietic-specific deficiency of Hif2α ameliorated pathological neovascularization in the OIR model, which was accompanied by enhanced endothelial cell apoptosis. That latter finding was associated with up-regulation of the apoptosis-inducer FasL in Hif2α-deficient microglia. Consistently, pharmacological inhibition of the FasL reversed the reduced pathological neovascularization from hematopoietic-specific Hif2α deficiency. Our study found that the hematopoietic cell Hif2α contributes to pathological retina angiogenesis. Our findings not only provide novel insights regarding the complex interplay between immune cells and endothelial cells in hypoxia-driven retina neovascularization but also may have therapeutic implications for proliferative retinopathies.-Korovina, I., Neuwirth, A., Sprott, D., Weber, S., Sardar Pasha, S. P. B., Gercken, B., Breier, G., El-Armouche, A., Deussen, A., Karl, M. O., Wielockx, B., Chavakis, T., Klotzsche-von Ameln, A. Hematopoietic hypoxia-inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis.

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A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity

Cited by 145 publications

References 65 publications

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Hematopoietic hypoxia‐inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis

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