Abstract
Macrophages are major players in the pathogenesis of pulmonary arterial hypertension (PAH).
To investigate whether lung macrophages and pulmonary-artery smooth muscle cells (PASMCs) collaborate 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 from murine M1 or M2 macrophages stimulated PASMC growth. This effect was markedly amplified with conditioned media 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 conditioned media 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 conditioned media 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.
Abstract
CCR2 and CCR5 are required for collaboration between macrophages and pulmonary artery smooth muscle cells (PASMCs) to initiate and amplify PASMC proliferation. Dual targeting of CCR2 and CCR5 may hold promise for treating pulmonary artery hypertension. http://bit.ly/2L3izU6
Footnotes
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Conflict of interest: S. Abid has nothing to disclose.
Conflict of interest: E. Marcos has nothing to disclose.
Conflict of interest: A. Parpaleix has nothing to disclose.
Conflict of interest: V. Amsellem has nothing to disclose.
Conflict of interest: M. Breau has nothing to disclose.
Conflict of interest: A. Houssaini has nothing to disclose.
Conflict of interest: N. Vienney has nothing to disclose.
Conflict of interest: M. Lefevre has nothing to disclose.
Conflict of interest: G. Derumeaux has nothing to disclose.
Conflict of interest: S. Evans is an employee of Pfizer Inc.
Conflict of interest: C. Hubeau was an employee of Pfizer Inc., during the conduct of the study.
Conflict of interest: M. Delcroix has nothing to disclose.
Conflict of interest: R. Quarck has nothing to disclose.
Conflict of interest: S. Adnot has nothing to disclose.
Conflict of interest: L. Lipskaia has nothing to disclose.
Support statement: This study was supported by grants from the INSERM, Délégation à la Recherche Clinique de l'AP-HP, Fondation pour la Recherche Médicale (FRM), Legs Poix and Agence Nationale pour la Recherche ANR. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received December 5, 2018.
- Accepted June 27, 2019.
- Copyright ©ERS 2019