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Interleukin-33-Activated Islet-Resident Innate Lymphoid Cells Promote Insulin Secretion through Myeloid Cell Retinoic Acid Production

Published on Nov 1, 2017in Immunity21.522
· DOI :10.1016/j.immuni.2017.10.015
Elise Dalmas8
Estimated H-index: 8
(University of Basel),
Frank M. Lehmann2
Estimated H-index: 2
(University of Basel)
+ 18 AuthorsMarc Y. Donath60
Estimated H-index: 60
(University of Basel)
Abstract
Summary Pancreatic-islet inflammation contributes to the failure of β cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1β, and palmitate). IL-33 promoted β cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the β cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute β cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion.
  • References (48)
  • Citations (28)
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References48
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#1Sandra Kallert (University of Basel)H-Index: 4
#2Stephanie Darbre (University of Geneva)H-Index: 4
Last. Daniel D. Pinschewer (University of Basel)H-Index: 33
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Viruses trigger potent cytotoxic T cell responses, whereas anti-tumour immunity has been difficult to establish. Here the authors engineer a replicating viral delivery system for tumour-associated antigens, which induces alarmin release, innate activation and protective anti-tumour immunity in mice.
10 CitationsSource
The cytokine interleukin-33 was first identified as an inducer of type 2 immune responses. It has now been shown to have pleiotropic activities on multiple immune cell types and is involved in numerous infectious and inflammatory diseases, as described in this Review.
208 CitationsSource
#1Justin I. Odegaard (UCSF: University of California, San Francisco)H-Index: 28
#2Min-Woo Lee (UCSF: University of California, San Francisco)H-Index: 2
Last. Ajay Chawla (UCSF: University of California, San Francisco)H-Index: 38
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Summary For placental mammals, the transition from the in utero maternal environment to postnatal life requires the activation of thermogenesis to maintain their core temperature. This is primarily accomplished by induction of uncoupling protein 1 (UCP1) in brown and beige adipocytes, the principal sites for uncoupled respiration. Despite its importance, how placental mammals license their thermogenic adipocytes to participate in postnatal uncoupled respiration is not known. Here, we provide evi...
48 CitationsSource
#1Yoichiro Ohne (MedImmune)H-Index: 3
#2Jonathan S. Silver (MedImmune)H-Index: 16
Last. Yong-Jun Liu (MedImmune)H-Index: 9
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Cytokines of the IL-1 family have a range of effects on innate lymphoid cells. Liu and colleagues find that IL-1 facilitates the maturation and plasticity of group 2 innate lymphoid cells.
124 CitationsSource
#1Steven E. Trasino (Cornell University)H-Index: 5
#2Xiao-Han Tang (Cornell University)H-Index: 12
Last. Lorraine J. Gudas (Cornell University)H-Index: 60
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To investigate the effects of specific retinoic acid receptor (RAR) agonists in diabetes and fatty liver disease.Synthetic agonists for RARβ2 were administered to wild-type (wt) mice in a model of high-fat-diet (HFD)-induced type 2 diabetes (T2D) and to ob/ob and db/db mice (genetic models of obesity-associated T2D).We show that administration of synthetic agonists for RARβ2 to either wt mice in a model of HFD-induced T2D or to ob/ob and db/db mice reduces hyperglycaemia, peripheral insulin resi...
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#1Shingo Kajimura (UCSF: University of California, San Francisco)H-Index: 43
#2Bruce M. Spiegelman (Harvard University)H-Index: 165
Last. Patrick Seale (UPenn: University of Pennsylvania)H-Index: 43
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Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that ...
262 CitationsSource
#1Justin I. Odegaard (UCSF: University of California, San Francisco)H-Index: 28
#2Ajay Chawla (UCSF: University of California, San Francisco)H-Index: 38
Adipose tissue resident leukocytes are often cast solely as the effectors of obesity and its attendant pathologies; however, recent observations have demonstrated that these cells support and effect ‘healthy’ physiologic function as well as pathologic dysfunction. Importantly, these two disparate outcomes are underpinned by similarly disparate immune programs; type 2 responses instruct and promote metabolic normalcy, while type 1 responses drive tissue dysfunction. In this Review, we summarize t...
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#1Boris CalderonH-Index: 22
#2Javier A. CarreroH-Index: 24
Last. Emil R. UnanueH-Index: 86
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We examine the features, origin, turnover, and gene expression of pancreatic macrophages under steady state. The data distinguish macrophages within distinct intrapancreatic microenvironments and suggest how macrophage phenotype is imprinted by the local milieu. Macrophages in islets of Langerhans and in the interacinar stroma are distinct in origin and phenotypic properties. In islets, macrophages are the only myeloid cells: they derive from definitive hematopoiesis, exchange to a minimum with ...
84 CitationsSource
#1Kimberly G. Riley (Vandy: Vanderbilt University)H-Index: 2
#2Raymond C. Pasek (Vandy: Vanderbilt University)H-Index: 10
Last. Maureen GannonH-Index: 39
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Objective Promotion of endogenous β-cell mass expansion could facilitate regeneration in patients with diabetes. We discovered that the secreted protein CTGF (aka CCN2) promotes adult β-cell replication and mass regeneration after injury via increasing β-cell immaturity and shortening the replicative refractory period. However, the mechanism of CTGF-mediated β-cell proliferation is unknown. Here we focused on whether CTGF alters cells of the immune system to enhance β-cell replication.
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#1Ari B. Molofsky (UCSF: University of California, San Francisco)H-Index: 18
#2Frédéric Van Gool (UCSF: University of California, San Francisco)H-Index: 12
Last. Richard M. Locksley (UCSF: University of California, San Francisco)H-Index: 95
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Summary Group 2 innate lymphoid cells (ILC2s) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show that interleukin-33 (IL-33) mediates activation of ILC2s and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation in vivo and was i...
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#1Lucie Orliaguet (Paris V: Paris Descartes University)H-Index: 1
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Although it has long been known that adipose tissue (AT) is involved in infection, interest in this topic is now growing. Although white AT can contribute to anti-infectious immune responses, it can also be targeted and perturbed by pathogens. The AT’s immune involvement is primarily due to strong pro-inflammatory responses (with both local and paracrine effects), and the large number of fat-resident macrophages. Adipocytes also exert direct antimicrobial responses. In recent years, it has been ...
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Inflammation must be effective, while limiting excessive tissue damage. To walk this line, immune functions are grossly compartmentalized by innate cells that act locally and adaptive cells that function systemically. But what about the myriad tissue-resident immune cells that are critical to this balancing act and lie on a spectrum of innate and adaptive immunity? We propose that mammalian perivascular adventitial ‘cuffs’ are conserved sites in multiple organs, enriched for these tissue-residen...
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