ADAM9 Promotes Glycolysis in Th17 Cells and Autoimmunity Through Activation of IGF-1 Signaling

Interleukin-17-producing CD4⁺ Th17 cells contribute to the pathogenesis of autoimmune diseases, including crescentic glomerulonephritis. Although ADAM9 has been reported to contribute to organ inflammation, the mechanism remains poorly understood. The goal of the current study was to investigate how ADAM9 alters T cell metabolism to promote the generation of Th17 cell differentiation.

We induced antiglomerular basement membrane (anti-GBM) glomerulonephritis in Adam9^+/+ and Adam9^-/- mice using sheep anti-GBM IgG and compared disease severity. Glycolysis in Th17 cells was measured using a Seahorse XFp Extracellular Flux Analyzer (Agilent Technologies, Inc), and metabolomic analysis was conducted on Th17 cells from both Adam9^+/+ and Adam9^-/- mice. We measured the GLUT1 expression in Th17 cells from Adam9^+/+ and Adam9^-/- mice and insulin-like growth factor 1 (IGF-1)-treated Th17 cells. Finally, we assessed the protease activity of ADAM9 on IGF-binding protein 4 (IGFBP4).

Mice deficient in ADAM9 had limited numbers of kidney-infiltrating CD4⁺ T cells and suffered reduced kidney damage and inflammation following the injection of sheep anti-GBM IgG. ADAM9 deficiency led to decreased GLUT1 expression and glycolysis in Th17 cells. Mechanistically, we found that ADAM9 cleaved IGFBP4 and enabled the release of IGF-1, which enhanced the expression of GLUT1 and promoted glycolysis.

By cleaving IGFBP4, ADAM9 releases IGF-1, which in turn upregulates GLUT1 expression and promotes glycolysis in Th17 cells. These findings suggest that targeting ADAM9 or blocking IGF-1 should provide a therapeutic strategy for autoimmune diseases.