Contributions of innate type 2 inflammation to adipose function

Abstract

A critical contributor to the health consequences of the obesity epidemic is dysregulated adipose tissue (AT) homeostasis. While white, brown, and beige AT function is altered in obesity-related disease, white AT is marked by progressive inflammation and adipocyte dysfunction and has been the focus of extensive "immunometabolism" research in the past decade. The exact triggering events initiating and sustaining AT inflammation are still under study, but it has been shown that reducing inflammation improves insulin action in AT. Scientific efforts seeking interventions to mitigate obesity-associated AT inflammation continue, and many groups are now determining how lean healthy AT homeostasis is maintained in order to leverage these mechanisms as therapeutic targets. Such studies have revealed that an elaborate network of immune cells, cytokines, and other cellular mediators coordinate AT function. Recent studies elucidated the involvement of the innate immune system in AT homeostasis (e.g., beiging and insulin sensitivity), including M2-like macrophages, eosinophils, innate lymphoid type 2 cells, and several others. In this review, we summarize the existing literature on innate type 2 inflammation in AT; additionally, we draw attention to areas of debate where seemingly conflicting data promises to yield more surprising and elegant biology as studies continue to dissect AT physiology.

Keywords: adipose tissue; beiging; eosinophil; homeostasis; innate immune system; innate lymphoid type 2 cell; macrophage; obesity.

Fig. 1.

Summary of known and potential innate type 2 immune cell interactions in the regulation of AT homeostasis. Stimuli, such as helminth infection, caloric restriction, or cold exposure, can induce the expression of IL-33/IL-25 to drive ILC2 numbers and activation. ILC2s secrete IL-5 to increase eosinophil numbers, which, in concert with one another, produce IL-13 and/or IL-4 to maintain M2-like macrophages (M2MΦ) or polarize M1-like macrophages (M1MΦ) into M2 macrophages. While innervating nerves are classically understood as the primary source of AT catecholamines, controversial data suggests that M2 macrophages and eosinophils may also supply catecholamines via expression of TH. Sympathetic NAMs/SAMs tightly align with AT nerves and can both uptake and catabolize nerve-derived catecholamines, reducing the available pool. Regardless of the source, catecholamines induce a thermogenic active state in adipocytes of WAT known as beiging. Alternatively, ILC2s have been shown to induce beiging via methionine enkephalin peptides, independent of eosinophils and M2 macrophages.