STAT4: An Initiator of Meta-Inflammation in Adipose Tissue?
- Department of Genetics and Complex Diseases, Department of Nutrition, Division of Biological Sciences, Harvard School of Public Health, Boston, Massachusetts
- Corresponding author: Chih-Hao Lee, .
Metabolic regulation and immune signaling are closely linked, as evidenced by both the physical proximity between metabolic cells (e.g., adipocytes and hepatocytes) and resident macrophages as well as the progression of inflammation in metabolic syndrome. Contrasting the reactions to pathogen infections, meta-inflammation describes a novel type of low-grade, unresolvable immune response that is in the causal pathway to metabolic dysregulation (1). Although how meta-inflammation is initiated remains unclear, the T-helper cell type 1 (Th1)/Th2 (or M1/M2) paradigm provides a simplified view of how immune cells are involved in readjusting metabolic set points in response to nutrient intake (2). It appears that Th1 cytokines (e.g., interleukin [IL]-12 and interferon-γ [IFNγ]) or Th1 polarized immune cells promote insulin resistance, whereas Th2 signaling (e.g., IL-4 and IL-13) sustains metabolic homeostasis (3). In mouse genetic models, for example, tipping the Th1/Th2 balance toward one specific spectrum leads to the expected outcome (4). As such, immunometabolism has become an attractive target to treat metabolic diseases.
Members of the signal transducer and activator of the transcription (STAT) family are transcription factors that mediate the signaling events of many cytokines in immune and nonimmune cells (5–7). The seven mammalian STAT proteins each contain a DNA-binding domain, a transactivation domain, and an Src homology 2 (SH2) domain; the latter is required for dimerization (5). When cytokines are bound to cell …