3.2 Th17 Cells
Th17 cells are a new class of CD4+ T cell subpopulation involved in differentiation and development. This cell type is strongly reliant on differentiation factors such as transforming growth factor-beta (TGF-β) or IL-6, and transcription factors such as STAT and retinoic acid receptor-related orphan receptors (ROR)γt, and RORα. They are mainly characterized by the secretion of IL-17, IL-22, and IL-2138. Th17 cells are involved in intestinal inflammation in rodents39; they proliferate and worsen adipose inflammation in diet-induced obesity in mice40, increase IL-17 and other Th17 factors in the liver41, and promote hepatic inflammation and fibrosis42. In addition, patients with T2DM have elevated levels of IL-17 in the peripheral blood43,44. Tissue inflammation and IR brought on by Th17 cells are linked to the development of T2DM, suggesting that obesity-induced Th17 cell amplification plays an essential role in the crosstalk between immunity and metabolism.
IL-6 is involved in skeletal muscle45 and adipocyte IR46, and inhibition of the IL-6/JAK2/STAT3 pathway restores Th17 cell and regulatory T cell (Treg) homeostasis and attenuates inflammatory responses47. Further investigation of the mechanism revealed that IL-17 promotes the expression of inflammatory cytokines through activation of TANK-binding kinase 1 (TBK1) and I-kappa-B kinase epsilon (IKBKE)48. Activation of NF-κB/p53/Rb signaling triggers inflammation to promote endothelial cell senescence and injury49. Inhibition of NF-κB and STAT activation disrupts IKBKE-driven cytokine expression50. In addition, insulin and insulin-like receptor 1 act synergistically with the inflammatory factor IL-17, together promoting the phosphorylation of glycogen synthase kinase 3 alpha and beta51. Therefore, Th17 cells may induce a range of metabolic disorders through secreted factors and inflammatory cells that interfere with immune homeostasis in the fat, liver, and gut. In addition, Th17 cells inhibit the activity of kinases downstream of glycogen synthesis and promote the onset and progression of T2DM. However, the study of Th17 on pancreatic islet function remains unclear.