Interleukin-22–STAT3 Signaling Preserves Structural Integrity in the Pressure-Overloaded Right Ventricle
K Shibao, H Yasukawa, D Zhehestovska, K Shima, Y FukumotoAbstract
Background
Right ventricular (RV) fibrosis and remodeling are linked to outcomes in RV failure. Interleukin-22 (IL-22), an IL-10 family cytokine, is involved in tissue protection and wound repair, but its contribution to RV remodeling during pressure overload is not well defined.
Purpose
To clarify the role of IL-22 in pressure overload–induced RV remodeling.
Methods
Pulmonary artery constriction (PAC) was created in wild-type (WT; C57BL/6J) and IL-22 knockout (IL-22 KO) mice using a 6-0 suture tied around the pulmonary artery over a 24G needle. Only mice with moderate stenosis (peak Doppler gradient >25 mmHg at 1 week) were analyzed. RV function and histology were assessed at 4 weeks. RV transcriptomics was performed (EdgeR, p<0.05), and survival was followed for up to 56 days.
Results
After PAC, IL-22 KO mice showed higher 56-day mortality than WT (p<0.01) and developed more pronounced RV dilatation and dysfunction at 4 weeks (RVEDV 10±2.3 vs 12.9±3.1 mm², p<0.01; FAC 35.2±7.8% vs 23.0±6.0%, p<0.01). Tricuspid regurgitation was also more common in IL-22 KO mice (100% vs 30%, p<0.01). Despite this functional deterioration, transcriptome analysis showed attenuated induction of extracellular matrix genes (e.g., Col3a1, Col5a2) and elastic fiber–related genes (Fbn1, Loxl1, Eln) in IL-22 KO mice. Histology supported these findings, with smaller fibrotic and elastic fiber areas in IL-22 KO mice at 4 weeks (Picro-Sirius red and resorcin-fuchsin staining; fibrotic area 31.2±5.8% vs 21.2±9.1%, p=0.01; elastic fiber area 11.5±4.1% vs 6.9±3.7%, p=0.46). In WT hearts, IL-22RA1–positive fibroblasts were abundant within fibrotic regions. At 1 week after PAC, Western blotting showed lower pSTAT3 levels in IL-22 KO than in WT.
Conclusions
This study suggests that fibrosis in the pressure-overloaded right ventricle is not uniformly detrimental and may represent an adaptive response required to preserve chamber architecture. IL-22–STAT3 signaling may support this adaptive extracellular matrix and elastic fiber response, thereby limiting right ventricular dilatation and the progression to severe tricuspid regurgitation.