Objective: Autoimmune diseases, such as systemic lupus erythematosus (SLE), are associated with pulmonary arterial hypertension (PAH), a condition that can lead to heart failure. However, whether T cells also contribute to the occurrence of PAH in SLE, has not been clarified. The objective of this study was to elucidate the role of Activin A signaling in the effector cells mainly involved in SLE-PAH. Methods: CyTOF analysis was performed to identify the major affected immune cell population after the treatment in SLE-PAH patients. ELISA showed the serum Activin A and IL-17 levels were significantly higher in patients with SLE-PAH compared to SLE alone and healthy donors. We also conducted Th17 cells coculturing with pulmonary microvascular endothelial cells(PMECs) and constructed a SLE-PH mouse model and CD4+ T cells depletion mice together with two rat models to identify the converged target. Results: The reduced CD4+ T cell number was detected in SLE-PAH patients after treatment. Activin A signals via ALK4 in both Th17 cells and PMECs. When ALK4 was overexpressed in Th17 cells, IL-6 and CTGF gene expression was significantly increased in cocultured PMECs. We found severe SLE-PH in mice by overexpression ALK4, and alleviated hemodynamic changes in CD4+ T cells depletion mice. ALK4 inhibitor TEW is effective to treat PAH by repressing CTGF transcription, which was facilitated by synergistic increases in pSmad2 and pSTAT3 levels downstream of ALK4 activation. Conclusion: Our findings suggest that Activin A activates ALK4 in Th17 cells to induce IL-17 secretion, meanwhile activated ALK4 via Smad2 phosphorylation to induce EndoMT in hPMECs, indicating that ALK4 is a promising therapeutic target for SLE-PAH.

The authors have declared no competing interest.

This work was supported by the Nature Science Foundation of China (Grant number 82470431) and the National Key Research and Development Program of China (Grant number 2023YFC2507100, 2021YFA1100500).

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