Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose Homeostasis

Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143-0795, USA.
Science (Impact Factor: 33.61). 03/2011; 332(6026):243-7. DOI: 10.1126/science.1201475
Source: PubMed


Eosinophils are associated with helminth immunity and allergy, often in conjunction with alternatively activated macrophages (AAMs). Adipose tissue AAMs are necessary to maintain glucose homeostasis and are induced by the cytokine interleukin-4 (IL-4). Here, we show that eosinophils are the major IL-4-expressing cells in white adipose tissues of mice, and, in their absence, AAMs are greatly attenuated. Eosinophils migrate into adipose tissue by an integrin-dependent process and reconstitute AAMs through an IL-4- or IL-13-dependent process. Mice fed a high-fat diet develop increased body fat, impaired glucose tolerance, and insulin resistance in the absence of eosinophils, and helminth-induced adipose tissue eosinophilia enhances glucose tolerance. Our results suggest that eosinophils play an unexpected role in metabolic homeostasis through maintenance of adipose AAMs.

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Available from: Ari Molofsky, Mar 29, 2014
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    • "These changes are associated with a shift in the function and population of normal WAT immune cells, characterized by diminished ILC2 activation and decreased numbers of eosinophils, AAM, and Tregs (Kolodin et al., 2015; Molofsky et al., 2015; Vasanthakumar et al., 2015). Each of these cell types has been shown to protect in mouse models of obesity-induced insulin resistance (Brestoff and Artis, 2015; Mathis, 2013; Wu et al., 2011), supporting the concept whereby IL-33 sustains the architecture and function of ST2 + resident cells that limit infiltration of adipose tissue by inflammatory lymphocytes and myeloid cells that lead to insulin resistance and metabolic syndrome. Although WAT is responsible for lipid storage, brown adipose tissue (BAT) expresses high amounts of uncoupling protein 1 (UCP1) and converts energy into heat, an important component of cold adaptation. "
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    ABSTRACT: Interleukin-33 (IL-33) is a nuclear-associated cytokine of the IL-1 family originally described as a potent inducer of allergic type 2 immunity. IL-33 signals via the receptor ST2, which is highly expressed on group 2 innate lymphoid cells (ILC2s) and T helper 2 (Th2) cells, thus underpinning its association with helminth infection and allergic pathology. Recent studies have revealed ST2 expression on subsets of regulatory T cells, and for a role for IL-33 in tissue homeostasis and repair that suggests previously unrecognized interactions within these cellular networks. IL-33 can participate in pathologic fibrotic reactions, or, in the setting of microbial invasion, can cooperate with inflammatory cytokines to promote responses by cytotoxic NK cells, Th1 cells, and CD8(+) T cells. Here, we highlight the regulation and function of IL-33 and ST2 and review their roles in homeostasis, damage, and inflammation, suggesting a conceptual framework for future studies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 06/2015; 42(6):1005-1019. DOI:10.1016/j.immuni.2015.06.006 · 21.56 Impact Factor
    • "Conversely, in lean individuals adipose tissue is infiltrated by alternatively activated macrophages (AAM) that reduce inflammation and promote insulin sensitivity through an IL-10 and regulatory T cell-mediated process [6]. Experimental studies have shown that eosinophils infiltrating adipose tissue are central to recruiting and maintaining AAM through IL-4 and IL-13, and that Th2 responses and eosinophilia in mice with experimental helminth infections are capable of increasing insulin sensitivity [28]. "
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    ABSTRACT: Objective: To explore the relationship between infection with Strongyloides stercoralis and the likelihood of having type 2 diabetes mellitus (T2DM). Methods: Cross-sectional survey of 259 Aboriginal adults living in a remote community in northern Australia during 2013. Prior infection with S. stercoralis was determined by ELISA testing on serum. Main outcomes were eosinophil count, T2DM diagnosis, HbA1c, BMI, fasting lipids, Hb, blood pressure. Findings: Ninety two participants (36%) had prior infection with S. stercoralis and 131 (51%) had T2DM. Those with previous S. stercoralis infection (ELISA titre >= 0.3) were 61% less likely to have a diagnosis of T2DM than those uninfected, adjusted for age, triglycerides, blood pressure and BMI using propensity score (adjusted OR = 0.39, 0.23-0.67, P = 0.001). Interpretation: In this remote community where prevalence of both S. stercoralis and T2DM is very high, infection with S. stercoralis appears to be associated with a significantly reduced risk of T2DM in adults. A plausible immunological mechanism has been identified in animal models. If confirmed, this result may have practical implications for the prevention of T2DM and associated metabolic disorders in humans. This finding should be explored further with larger longitudinal studies in transitional populations where the risk of both conditions is high. Funding: No external funding was required for this study.
    Diabetes Research and Clinical Practice 01/2015; 107(3). DOI:10.1016/j.diabres.2015.01.012 · 2.54 Impact Factor
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    • "Recent work has highlighted a previously unappreciated role for ILC2s in mediating metabolic homeostasis in adipose tissue. Type 2 cytokine-associated eosinophil responses regulate AAMs to promote glucose and adipose tissue homeostasis (Wu et al. 2011) and ILC2s have recently been shown to regulate this process via production of IL-5 and its effect on eosinophil survival (Fig. 4) (Molofsky et al. 2013). In support of these findings, IL-33 was shown to limit obesity in mice (Miller et al. 2010), whereas another study showed that IL-25 elicits ILC2s to limit obesity (Hams et al. 2013). "
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    ABSTRACT: Group 2 innate lymphoid cells (ILC2s) play critical roles in anti-helminth immunity, airway epithelial repair, and metabolic homeostasis. Recently, these cells have also emerged as key players in the development of allergic inflammation at multiple barrier surfaces. ILC2s arise from common lymphoid progenitors in the bone marrow, are dependent on the transcription factors RORα, GATA3, and TCF-1, and produce the type 2 cytokines interleukin (IL)-4, IL-5, IL-9, and/or IL-13. The epithelial cell-derived cytokines IL-25, IL-33, and TSLP regulate the activation and effector functions of ILC2s, and recent studies suggest that their responsiveness to these cytokines and other factors may depend on their tissue environment. In this review, we focus on recent advances in our understanding of the various factors that regulate ILC2 function in the context of immunity, inflammation, and tissue repair across multiple organ systems. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 01/2015; 7(5). DOI:10.1101/cshperspect.a016337 · 8.68 Impact Factor
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