Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose Homeostasis

Abstract

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 by an integrin-dependent process and reconstitute AAMs through an IL-4/IL-13-dependent process. Mice on high-fat diet develop increased body fat, impaired glucose tolerance and insulin resistance in the absence of eosinophils, and helminth-induced adipose eosinophilia enhances glucose tolerance. Our results suggest that eosinophils play an unexpected role in metabolic homeostasis through maintenance of adipose AAMs.

Obesity-Associated Adipose Tissue Inflammation and Transplantation

“…Using a strain of IL-4 reporter mice, Molofsky et al reported that more than 85% of the IL-4-producing cells in lean AT are eosinophils, immune cells that are dependent on IL-5 and IL-13 for growth and survival (12). Mice lacking eosinophils develop severe HFD-induced obesity and insulin resistance and have significantly lower numbers of M2 macrophages (12). iNKT cells resident in AT are also a major source of IL-4.…”

IL‐33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells

“…Eosinophils are located in visceral adipose tissue, and the loss of eosinophils leads to a decrease in alternatively activated macrophage (AAM) accumulation [2]. AAMs in gonadal adipose tissue (GAT) are maintained by IL-4 and/or IL-13 [3]. The activation of eosinophils critically depends on IL-5: studies using il5-tg mice or il5-deficient mice and anti-IL-5 Ab have demonstrated that the expansion of eosinophils is largely regulated by IL-5 [4][5][6][7][8].…”

“…Eosinophils also play critical roles in metabolic homeostasis relating to obesity [2]. GATA-1 is critical to eosinophil development, and dblGATA mice, in which the GATA binding sites in the Gata1 promoter are mutated, are prone to obesity when fed a high-fat diet [2,3]. Eosinophils are located in visceral adipose tissue, and the loss of eosinophils leads to a decrease in alternatively activated macrophage (AAM) accumulation [2].…”

“…7 and 8A). Although the precise mechanisms how IL-33 regulates adipose tissue remains unknown, it is reported that eosinophils control adipose AAMs, which plausibly regulate adipose [3]. IL-33 is an important cytokine which activates eosinophils [2,19].…”

“…Il5-deficient mice show higher body weight and visceral adipose weight in response to a highfat diet [2]. Deficiency of il5 or eosinophils impairs glucose consumption and promotes obesity [2] and adipose tissue metabolism is thus regulated by eosinophils through the activation of AAMs [2,3,9].Innate lymphoid cells (ILCs) play a protective role against foreign pathogens [10]. ILCs are classified into at least three groups, depending on the cytokines produced [11].…”