Targeting CCR2 and CCR5 to inhibit macrophage/pulmonary artery smooth muscle cells cross-talk in pulmonary hypertension
EUROPEAN RESPIRATORY JOURNAL(2018)
Abstract
Macrophages (MΦ) are major players in the pathogenesis of pulmonary hypertension (PH) but the way they interact with pulmonary artery smooth muscle cells (PASMC) remains poorly understood. We questioned whether lung MΦ and PASMC collaborate to stimulate PASMC growth and targeting simultaneously the CCL2-CCR2 & CCL5-CCR5 axis inhibits MΦ/PASMC interactions and PH development. Conditioned media (CM) derived from murine M1 or M2-MΦ stimulated the PASMC growth and this effect was greatly amplified by using CM from MΦ co-cultured with PA-SMC, with greater effects of M2- than M1-MΦ. Co-culturing MΦ and PASMC caused upregulation of CCR2 & CCR5 in both MΦ and PASMC and of their ligands CCL2 & CCL5. Dual CCR2 & CCR5 inhibition attenuated the growth promoting effect of CM from co-cultured M2-MΦ/PASMC more than inhibiting CCR2 or CCR5 individually. Deletion of either CCR2 or CCR5 in MΦ or PASMC attenuated the response. In mice with hypoxia or SUGEN-hypoxia induced PH, exhibiting increased lung CCR2 & CCR5 expression in MΦ and PASMC, dual targeting of CCR2 & CCR5 prevented or reversed PH more efficiently. Patients with PAH compared to controls exhibited upregulaton of CCR2 & CCR5 in PASMC and perivascular MΦ. CM from co-cultured M2-MΦ/PASMC resulted in a marked stimulation of growth with a further stimulatory effect when PASMC from PAH patients were used instead of controls. These effects were amplified by using PASMC from patients with PAH as target cells. Treatment with the dual CCR2-CCR5 antagonist in all cases attenuated the response. Collaboration between MΦ and PASMC requires CCR2 & CCR5, thus dual targeting of CCR2 & CCR5 is a promising strategy for treating human PH.
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Key words
macrophage/pulmonary hypertension,macrophage/pulmonary artery,ccr2,ccr5,smooth muscle cells,cross-talk
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