Roles for the CX3CL1/CX3CR1 and CCL2/CCR2 Chemokine Systems in Hypoxic Pulmonary Hypertension

Abstract

Monocytes/macrophages are major effectors of lung inflammation associated with various forms of pulmonary hypertension (PH). Interactions between the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine systems that guide phagocyte infiltration are incompletely understood. Our objective was to explore the individual and combined actions of CCL2/CCR2 and CX3CL1/CX3CR1 in hypoxia-induced PH in mice; particularly their roles in monocyte trafficking, macrophage polarization, and pulmonary vascular remodeling. The development of hypoxia-induced PH was associated with marked increases in lung levels of CX3CR1, CCR2, and their respective ligands, CX3CL1 and CCL2. Flow cytometry revealed that both inflammatory Ly6C and resident Ly6C monocyte subsets exhibited sustained increases in blood and a transient peak in lung tissue, and that lung perivascular and alveolar macrophage counts showed sustained elevations. CX3CR1 mice were protected against hypoxic PH compared with wild-type mice, whereas CCL2 mice and double CX3CR1/CCL2 mice exhibited similar PH severity, as did wild-type mice. The protective effects of CX3CR1 deficiency occurred concomitantly with increases in lung monocyte and macrophage counts and with a change from M2 to M1 macrophage polarization that markedly diminished the ability of conditioned media to induce pulmonary artery smooth muscle cell (PA-SMC) proliferation, which was partly dependent on CX3CL1 secretion. Results in mice given the CX3CR1 inhibitor F1 were similar to those in CX3CR1 mice. In conclusion, CX3CR1 deficiency protects against hypoxia-induced PH by modulating monocyte recruitment, macrophage polarization, and PA-SMC cell proliferation. Targeting CX3CR1 may hold promise for treating PH.

Uric Acid Has Direct Proinflammatory Effects on Human Macrophages by Increasing Proinflammatory Mediators and Bacterial Phagocytosis Probably via URAT1

“…On the contrary, the exposure of macrophages to dexamethasone or cytokines, such as interleukin IL-4 and IL-13, leads these cells to adopt an anti-inflammatory profile that is characterized by the production of IL-10 and/or CD206 [15]. Furthermore, the exposure of macrophages to proor anti-inflammatory stimuli also affects the expression of molecules that are involved in leukocyte trafficking, such as CX3C-motif chemokine receptor 1 (CX3CR1) and C-C chemokine receptor type 2 (CCR2) [17,18]. More importantly, the inflammatory activation enhances the ability of macrophages to ingest bacteria with respect to that described in macrophages with anti-inflammatory functions [19,20].…”

Myeloid-Derived Suppressor Cells and Pulmonary Hypertension

“…Additionally, other cell-surface chemokine receptors commonly expressed by Mo-MDSC, such as CCR2 and CX3CR1, are highly expressed in circulating immune cells accumulating within the lungs of mice with chronic hypoxia-induced pulmonary hypertension [79]. A direct role, however, for secreted CCR2 and CX3CR1 ligands in regulating the hemodynamic changes, beyond recruitment of inflammatory monocytes and indirect influence on pulmonary artery smooth muscle cell hyperproliferation, remains unproven [80].…”

Origin and production of inflammatory perivascular macrophages in pulmonary hypertension

“…The importance of monocyte infiltration into the lungs in PH is relatively understudied. Recently, Amsellem et al showed that Cx 3 cr1 plays a major role in hypoxia-induced PH by modulating monocyte recruitment, macrophage polarization, and smooth muscle cell proliferation in the lungs[75]. Congruently, cx 3 cr1 -deficient mice had an attenuated PH pathogenesis.…”

“…For example, in the context of atherosclerosis, high levels of G-CSF suppress CXCL12 production by osteoblasts, leading to HSC proliferation and release [94, 95]. As discussed above, multiple studies reported blood and lung monocytosis in the context of PH [62, 75, 76]. The blood monocyte expansion depends on their generation in the bone marrow from hematopoietic stem and progenitor cells.…”

“…B) Reduction of monocyte numbers in the lungs: Monocyte numbers in the lungs could be reduced in two different ways: a) inhibition of monocyte egress from the bone marrow and b) suppressing monocyte recruitment into the lungs. Chemokine receptors, such as CX 3 CR1 and CCR2, play crucial roles in monocyte egress and recruitment [75]. We successfully blocked monocyte egress from the bone marrow in mouse models of myocardial infarction and atherosclerosis using siRNA against CCR2 [112].…”