IL-22BP attenuates right ventricular remodeling in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease in which right ventricular (RV) dysfunction and remodeling are major determinants of poor prognosis. Interleukin-22 binding protein (IL-22BP), encoded by IL22RA2/Il22ra2, is an endogenous antagonist of IL-22, but its role in PAH-associated RV remodeling remains unclear. Here, we investigated whether IL-22BP regulates RV remodeling through the IL-22/STAT3 axis. Serum IL-22BP levels were reduced in patients with PAH. In experimental PAH, RV IL-22BP was decreased in Sugen5416/hypoxia (SuHx) and monocrotaline rat models, and both RV Il22ra2 mRNA and IL-22BP protein were reduced in SuHx mice. In the SuHx mouse model, systemic Il22ra2 deficiency aggravated PAH severity and RV remodeling, accompanied by enhanced RV IL-22/IL-22R1/STAT3 signaling and increased remodeling-associated transcripts related to hypertrophy, fibrosis, apoptosis, and proliferation. Conversely, AAV-mediated IL-22BP reconstitution with preferential cardiac expression attenuated RV hypertrophy and dysfunction and suppressed RV IL-22/STAT3 signaling. Pharmacological STAT3 inhibition with S3I-201 partially rescued the aggravated PAH and RV remodeling phenotype in SuHx-treated Il22ra2-/- mice. Complementary H9C2 cell experiments showed that IL-22 enhanced Ang II-associated STAT3 activation and remodeling-related transcriptional responses, whereas S3I-201 attenuated several Ang II-induced remodeling signals. Lung analysis showed altered pulmonary IL-22/STAT3 signaling after SuHx exposure and Il22ra2 deficiency, but cardiac IL-22BP reconstitution did not significantly normalize these whole-lung markers. Th17-related immune changes paralleled disease severity and IL-22BP-associated improvement. Finally, treprostinil plus oridonin produced broader phenotypic improvement than either monotherapy and increased cardiac IL-22BP expression. These findings identify IL-22BP as a treatment-responsive endogenous regulator of PAH-associated RV remodeling.