CCR2/CCR5-mediated macrophage-smooth muscle cell crosstalk in pulmonary hypertension.
Adolescent
Adult
Animals
Cell Communication
Cell Movement
/ genetics
Cell Proliferation
/ genetics
Coculture Techniques
Culture Media, Conditioned
Disease Models, Animal
Female
Gene Knock-In Techniques
Humans
Macrophages
/ metabolism
Male
Mice
Mice, Knockout
Middle Aged
Muscle, Smooth, Vascular
/ cytology
Myocytes, Smooth Muscle
/ metabolism
Pulmonary Arterial Hypertension
/ genetics
Pulmonary Artery
/ cytology
Receptors, CCR2
/ genetics
Receptors, CCR5
/ genetics
Young Adult
Journal
The European respiratory journal
ISSN: 1399-3003
Titre abrégé: Eur Respir J
Pays: England
ID NLM: 8803460
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
05
12
2018
accepted:
27
06
2019
pubmed:
20
7
2019
medline:
8
10
2020
entrez:
20
7
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31320454
pii: 13993003.02308-2018
doi: 10.1183/13993003.02308-2018
pii:
doi:
Substances chimiques
CCR2 protein, human
0
CCR5 protein, human
0
CCR5 protein, mouse
0
Ccr2 protein, mouse
0
Culture Media, Conditioned
0
Receptors, CCR2
0
Receptors, CCR5
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright ©ERS 2019.
Déclaration de conflit d'intérêts
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.