Blocking the aryl hydrocarbon receptor (AhR) protects CD4+ T cells from Th17/Treg differentiation imbalance through SENP1-mediated deSUMOylation.

BACKGROUND

Immune thrombocytopenic purpura (ITP) is the most common autoimmune bleeding disorder in children and poses a serious threat to pediatric health and survival. An imbalance in Th17 and Treg cell differentiation leads to uncontrolled inflammation.

METHODS

Peripheral blood mononuclear cells and CD4+ T cells were isolated from 23 ITP patients and 23 healthy controls. Th17 and Treg proportions were quantified by flow cytometry, and serum concentrations of IL-17 A, IL-10, IL-22, IL-23, IL-6, and TNF-α were measured by ELISA. An ITP mouse model was established by splenocyte transfer, and AhR antagonism was evaluated using CH-223191. AhR SUMOylation was assessed by co-immunoprecipitation and western blot, and transcriptional activity was determined by dual-luciferase reporter assay.

RESULTS

The Th17/Treg ratio was significantly elevated in ITP patients compared with controls (P < 0.001), accompanied by increased serum IL-17 A, IL-22, IL-23, IL-6, and TNF-α and decreased IL-10 (P < 0.001). AhR mRNA and protein expression were markedly upregulated in ITP CD4+ T cells (P < 0.001). Inhibition of AhR by CH-223191 reduced the Th17 proportion from 3.5% to 2.0% and increased the Treg proportion from 1.2% to 2.8%, normalizing the Th17/Treg ratio (P < 0.001). Consistent results were observed in vivo, with improved platelet counts and restored Th17/Treg balance. Mechanistically, AhR underwent SUMOylation at K63 and K510 by SUMO1, which enhanced AhR protein stability and transcriptional activity; this modification was reversed by SENP1-mediated deSUMOylation.

CONCLUSION

Blocking AhR, which is modified by SUMO1 and deSUMOylated by SENP1, alleviates ITP-induced Th17/Treg imbalance through SENP1-mediated deSUMOylation.