Abstract
Interleukin-22 (IL-22) is a cytokine with important functions in host defense and inflammatory responses and has recently been suggested to play a role in immune-inflammatory system in the context of obesity and its metabolic consequences. The specific cellular targets and mechanisms of IL-22-mediated obesity are largely unknown however. We here identified a previously unknown subset of monocyte-derived Duffy antigen receptors for chemokines (DARC)+ macrophages in epididymal fat adipose tissue and found that they are preferentially recruited into the crown-like structures of adipose tissue in the mouse upon high fat diet-induced obesity. Importantly, DARC+ macrophages highly express the IL-22 receptor (IL-22Ra1). Exposure to recombinant IL-22 shifts macrophages to an alternative M2 polarization pathway and augments DARC expression via a STAT5b signaling axis. STAT5b directly binds to the DARC promoter and a STAT5 inhibitor abrogates the IL-22-mediated induction of DARC. These M2-like DARC+ subpopulations of monocytes/macrophages were elevated in obese db/db mice compared to WT lean mice. Furthermore, subsets of CD14+ and/or CD16+ monocytes/macrophages within human peripheral blood mononuclear cell populations express DARC and the prevalence of these subsets is enhanced by IL-22 stimuli. This suggested that IL-22 is a critical cytokine that promotes the infiltration of adipose tissue macrophages, that regulate inflammatory processes. Taken together, our present findings provide important insights into the molecular mechanism by which IL-22 signal modulates DARC expression in M2-like macrophages.
Highlights
Adipose tissue is involved in various biological functions including storage of excess energy, cold insulation, and the mechanical protection of the vital organs
It has been recently reported that CCL2 and CCL5 are linked to the obesity-associated infiltration by monocytes/macrophages of adipose tissues [34]
We found that the CCL2, atypical chemokine receptor 1 (Ackr1) (DARC), IL-1β, and IL-10 transcript levels were enhanced in epididymal white adipose tissue (eWAT) from the high fat diet (HFD)-fed mouse groups (Figure S1)
Summary
Adipose tissue is involved in various biological functions including storage of excess energy, cold insulation, and the mechanical protection of the vital organs. The adipose tissue produces and secretes a variety of cytokines, known as adipokines, principally from the immune cells in fat and functions as an endocrine organ for regulating immune-inflammatory responses [1,2]. Adipose tissue macrophages (ATMs) increase their cell number and change their phenotype such as localization and inflammatory features during obesity. Interleukin 22 (IL-22) is a recently identified small protein which has various functions, including the regulation of inflammatory responses, coordination between innate and adaptive immunity, modulation of metabolic alterations, epithelial cell integrity, and cell survival [27,28,29]. M2-like DARC+ macrophages that reside in the epididymal fat adipose tissues in mouse and peripheral blood mononuclear cells (PBMCs) in human subjects. Our present findings provide important insights into the molecular mechanism by which IL-22 signals regulate DARC expression in M2-like macrophages
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