Abstract
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.
