Activin A–Activated ALK4 Induces Pathogenic Th17‐Involved Endothelial–Mesenchymal Transition in Systemic Lupus Erythematosus–Associated Pulmonary Arterial Hypertension
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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
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.
Results
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.
Conclusion
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.
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