IL-22 mediated immuno-vascular crosstalk aggravates Ang II induced hypertension in mice via ferritinophagy

Distinct immune subsets have been demonstrated to participate in hypertensive vascular remodeling. This study investigated whether the aryl hydrocarbon receptor (AHR) plays a regulatory role in Angiotensin II (Ang II)-induced vascular injury via the regulation of Th22/IL-22 signaling and ferroptosis. Using a mouse model of Ang II-induced hypertension and vascular remodeling, we observed that the AHR antagonist CH-223191 significantly alleviated hypertension, aortic media thickens, and fibrosis. Mechanistically, AHR inhibition downregulated Th22 cell differentiation and suppressed the activation of the IL-22/STAT3 pathway, which subsequently inhibited oxidative stress and ferritinophagy in vascular smooth muscle cells (VSMCs). Conversely, the adoptive transfer of Th22 cells aggravated vascular remodeling and VSMC phenotypic switching. Furthermore, pharmacological inhibition of ferroptosis with Ferrostatin-1 phenocopied the protective effects of the AHR antagonist and reversed IL-22-induced phenotypic switching. In conclusion, AHR activation aggravates Ang II-induced vascular remodeling by promoting Th22 cell differentiation and IL-22/STAT3-mediated ferroptosis in VSMCs.