IL-21 and IRF4: A Complex Partnership in Immune and Metabolic Regulation

  1. Chih-Hao Lee
  1. Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard School of Public Health, Boston, MA
  1. Corresponding author: Chih-Hao Lee, clee{at}

Adipose tissue is comprised of a community of different immune cells that contributes to regulation of energy storage and release by adipocytes. The population of various immune cells is dynamic, undergoing phenotypic and compositional changes in response to physiologic (e.g., fasting vs. feeding) and pathologic (e.g., lean vs. obese) stimuli. Cumulative evidence suggests that a regulatory or anti-inflammatory immune phenotype promotes metabolic homeostasis, whereas a proinflammatory response is associated with metabolic dysregulation (1). Accordingly, lean, healthy white adipose tissue (WAT) is home to a population of alternatively activated macrophages (M2s) as well as immune cells that mediate M2 polarization, such as eosinophils, CD4+ T-helper type (Th) 2 cells, and regulatory T cells (Tregs) (1). During obesity, WAT is infiltrated by additional classically activated macrophages (M1s), neutrophils, mast cells, and CD8+ T cells that release proinflammatory cytokines, thereby sustaining metabolic inflammation, or meta-inflammation (2). Although the changes in immune repertoires associated with different metabolic states are well characterized, mechanisms underlying the switches in immune phenotypes remain unclear.

Due to their roles in skewing immune cell responses, multiple cytokines have been suggested to play a role in the development of meta-inflammation in obesity. The first studies to recognize that obesity is associated with inflammation identified tumor necrosis factor-α (TNFα) as a mediator of WAT insulin resistance. TNFα produced by infiltrating M1s triggers the activation of Jun NH2-terminal kinase and inhibitor of κB kinase β causing antagonistic phosphorylation of insulin receptor …

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