RT Journal Article
SR Electronic
T1 CCR2/CCR5-Mediated Macrophage-Smooth Muscle Cell Crosstalk in Pulmonary Hypertension
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1802308
DO 10.1183/13993003.02308-2018
A1 Shariq Abid
A1 Elisabeth Marcos
A1 Aurélien Parpaleix
A1 Valérie Amsellem
A1 Marielle Breau
A1 Amal Houssaini
A1 Nora Vienney
A1 Marine Lefevre
A1 Genevieve Derumeaux
A1 Steven Evans
A1 Cedric Hubeau
A1 Marion Delcroix
A1 Rozenn Quarck
A1 Serge Adnot
A1 Larissa Lipskaia
YR 2019
UL http://erj.ersjournals.com/content/early/2019/07/03/13993003.02308-2018.abstract
AB Macrophages are major players in the pathogenesis of pulmonary arterial hypertension (PAH). To investigate whether lung macrophages and pulmonary-artery smooth muscle cells (PASMCs) collaborated to stimulate PASMC growth and whether the CCL2-CCR2 and CCL5-CCR5 pathways inhibited macrophage-PASMC interactions and PAH development, we used human CCR5-knock-in mice and PASMCs from patients with PAH and controls. Conditioned media (CM) from murine M1 or M2 macrophages stimulated PASMC growth. This effect was markedly amplified with CM from M2 macrophage/PASMC co-cultures. CCR2, CCR5, CCL2, and CCL5 were upregulated in macrophage/PASMC co-cultures. Compared to inhibiting either receptor, dual CCR2 and CCR5 inhibition more strongly attenuated the growth-promoting effect of CM from M2-macrophage/PASMC co-cultures. Deleting either CCR2 or CCR5 in macrophages or PASMCs attenuated the growth response. In mice with hypoxia- or SUGEN/hypoxia-induced PH, targeting both CCR2 and CCR5 prevented or reversed PH more efficiently than targeting either receptor alone. Patients with PAH exhibited CCR2 and CCR5 upregulation in PASMCs and perivascular macrophages compared to controls. The PASMC growth-promoting effect of CM from M2-macrophage/PASMC co-cultures was greater when PASMCs from PAH patients were used in the co-cultures or as the target cells and was dependent on CCR2 and CCR5. PASMC migration toward M2-macrophages was greater with PASMCs from PAH patients and was attenuated by blocking CCR2 and CCR5.CCR2 and CCR5 are required for collaboration between macrophages and PASMCs to initiate and amplify PASMC migration and proliferation during PAH development. Dual targeting of CCR2 and CCR5 may hold promise for treating human PAH.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. ABID has nothing to disclose.Conflict of interest: Dr. Marcos has nothing to disclose.Conflict of interest: Dr. Parpaleix has nothing to disclose.Conflict of interest: Dr. Amsellem has nothing to disclose.Conflict of interest: Dr. Breau has nothing to disclose.Conflict of interest: Dr. Houssaini has nothing to disclose.Conflict of interest: Dr. Vienney has nothing to disclose.Conflict of interest: Dr. Lefevre has nothing to disclose.Conflict of interest: Dr. Derumeaux has nothing to disclose.Conflict of interest: Dr. Evans has nothing to disclose.Conflict of interest: Dr. Hubeau has nothing to disclose.Conflict of interest: Dr. Delcroix has nothing to disclose.Conflict of interest: Dr. Quarck has nothing to disclose.Conflict of interest: Dr. Adnot has nothing to disclose.Conflict of interest: Dr. Lipskaia has nothing to disclose.