Activin A‐activated ALK4 induces pathogenic Th17 involved endothelial–mesenchymal transition in systemic lupus erythematosus‐associated pulmonary arterial hypertension

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 and activated receptor signaling in SLE‐PAH. Methods CyTOF analysis was performed to identify the major affected immune cell population in SLE‐PAH patients. Serum Activin A and IL‐17 levels in patients with SLE‐PAH, SLE and healthy donors were determined by ELISA. Cocultures of Th17 cells with pulmonary microvascular endothelial cells (PMECs) and relevant rodent models were used to identify the converged target. Results The reduced CD4 + T cell number was detected in SLE‐PAH patients after treatment with immunosuppressant and vasodilator. Increased Th17 cells population, higher serum Activin A and IL‐17 levels were found in patients with SLE‐PAH compared to SLE or Donor. Activin A signals via ALK4 in both Th17 cells and PMECs. Overexpressing ALK4 in Th17 cells increased IL‐6 and endothelial–mesenchymal transition (EndoMT) marker levels in cocultured PMECs. We found severe SLE‐PH in mice by overexpressing ALK4, and alleviated hemodynamic changes in CD4 + T cells depletion mice. ALK4 inhibitor TEW effectively treated SLE‐PH mice by repressing CTGF transcription, which was induced by ALK4 activated pSmad2 and pSTAT3. Conclusion Our findings suggest that Activin A activates ALK4 in Th17 cells, thereby inducing IL‐17 secretion. Concurrently, activated ALK4 induces EndoMT in hPMECs via CTGF upregulation. It suggests that ALK4 is a promising therapeutic target for SLE‐PAH.