Differential Effects Of Cx3cr1 And Ccr2 Deficiencies In Hypoxic Pulmonary Hypertension

The development of hypoxia-induced pulmonary hypertension (PH) is associated with lung inflammation and vessel infiltration by monocytes. Two major monocyte subsets showing differential expression of CCR2 and CX3CR1 receptors have been identified. Ly6Chi monocytes are involved in inflammation and express high levels of CCR2 but low levels of CX3CR1 (Ly6Chi CCR2hi/CX3CR1lo). Ly6Clo monocytes are the noninflammatory subtype and express high levels of CX3CR1 (Ly6Cl°CCR2lo/CX3CR1hi). To determine the roles for Ly6Chi and Ly6Clo monocytes in hypoxic PH in mice, we studied CX3CR1-/-, CCL2-/− or double CX3CR1/CCL2-/− mice compared to wild type (WT) mice. Development of hypoxia-induced PH was associated with a marked increase in lung mRNA levels of CX3CR1, CCR2 and of their respective ligands CX3CL1 and CCL2. FACs analysis revealed sustained increases in both monocyte subsets in blood but only a transient peak on day 3 of hypoxia exposure in lung tissue. Total lung macrophage counts remained unchanged. CX3CR1-/− mice showed protection against hypoxic PH compared to WT mice, whereas CCL2-/− mice and double CX3CR1/CCL2-/− mice exhibited similar PH severity as did WT mice. Chronically hypoxic WT and mutant mice did not differ regarding lung Ly6Clo monocytes, whereas Ly6Chi counts were reduced in CCL2-/− or double CX3CR1/CCL2-/− mice compared to WT or CX3CR1-/− mice. Total lung macrophage counts did not differ between WT and CCL2-/− or double CX3CR1/CCL2-/− mice but were markedly increased in CX3CR1-/− mice. These results are consistent with previous studies showing that CCR2 deficiency exacerbates PH in hypoxic mice, and they support a prominent effect of the CX3CL1/CX3CR1 axis on pulmonary vascular remodeling. Accordingly, we found that CX3CL1 potentiated proliferation of cultured PA-SMCs from WT mice but not from CX3CR1-/− mice. CX3CR1 deficiency protects against hypoxia-induced PH by modulating monocyte recruitment and PA-SMC cell proliferation.