M2 macrophages derived from patients with idiopathic pulmonary arterial hypertension are susceptible for apelin-mediated suppression of pro-inflammatory cytokines

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Background: Apelin (APLN) and its receptor (APLN-R) have been indicated to influence inflammatory processes. The present analysis aimed (1) to demonstrate the possible involvement of alternatively activated (M2) macrophages to the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) and (2) to assess the effect of the APLN on M2 macrophages derived from IPAH patients. Methods: Monocytes were isolated from IPAH patients and age-gender-matched healthy subjects. Cells were labeled with BCECF to assess adherence to human pulmonary arterial endothelial cells (HPAEC). To generate M2 macrophages, monocytes were stimulated with M-CSF and IL-4. FACS was used to assess CD11b and APLN-R expression. Cytokine expression was assessed by proteome profiling and RT-PCR following stimulation with APLN. Results: Hypoxia and Th2-type cytokine IL-4 stimulated synergistically adhesion of monocytes isolated from IPAH patients to HPAEC. The effect of IL-4 was dose-dependent. In vitro generated CD11b+ M2 macrophages derived from IPAH patients demonstrated a significant increased expression of the APLN-R compared to healthy subjects (p<0.05; t-test; each group n=7). Stimulation of M2 macrophages with APLN attenuated the M2 phenotype and caused suppression of various cytokines including CCL5/Rantes and CCL2/MCP-1. Conclusion: We demonstrate that the Th2-pathway in patients with IPAH leads to an increased pulmonary arterial accumulation of monocytes. M2 macrophages derived from IPAH patients are susceptible for APLN-mediated suppression of cytokines. Our findings point out an anti-inflammatory action of APLN in IPAH.

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