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.