Activin A-Activated ALK4 Induces Pathogenic Th17-Involved Endothelial-Mesenchymal Transition in Systemic Lupus...

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.

Mass Cytometry (CyTOF) analysis was performed to identify the major affected immune cell population in patients with SLE-PAH. Serum Activin A and interleukin-17 (IL-17) levels in patients with SLE-PAH, patients with SLE, and healthy donors were determined by enzyme-linked immunosorbent assay. Cocultures of Th17 cells with pulmonary microvascular endothelial cells (PMECs) and relevant rodent models were used to identify the converged target.

The reduced CD4⁺ T cell number was detected in patients with SLE-PAH after treatment with immunosuppressant and vasodilator. Increased Th17 cells population and higher serum Activin A and IL-17 levels were found in patients with SLE-PAH compared to patients with SLE only or donors. Activin A signals via activin receptor-like kinase 4 (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-pulmonary hypertension (PH) in mice by overexpressing ALK4, and alleviated hemodynamic changes in CD4⁺ T cells depletion mice. ALK4 inhibitor vactosertib (TEW-7197) effectively treated SLE-PH mice by repressing connective tissue growth factor (CTGF) transcription, which was induced by ALK4 activated pSmad2 and pSTAT3.

Our findings suggest that Activin A activates ALK4 in Th17 cells, thereby inducing IL-17 secretion. Concurrently, activated ALK4 induces EndoMT in human PMECs (hPMECs) via CTGF up-regulation. It suggests that ALK4 is a promising therapeutic target for SLE-PAH.