Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends upon Mobilization of Blood-Borne Monocytes

Abstract

Pulmonary inflammation, which is characterized by the presence of perivascular macrophages, has been proposed as a key pathogenic driver of pulmonary hypertension (PH), a vascular disease with increasing global significance. However, the mechanisms of expansion of lung macrophages and the role of blood-borne monocytes in PH are poorly understood. Using multicolor flow cytometric analysis of blood in mouse and rat models of PH and patients with PH, an increase in blood monocytes was observed. In parallel, lung tissue displayed increased chemokine transcript expression, including those responsible for monocyte recruitment, such as and, accompanied by an expansion of interstitial lung macrophages. These data indicate that blood monocytes are recruited to lung perivascular spaces and differentiate into inflammatory macrophages. Correspondingly, parabiosis between congenically different hypoxic mice demonstrated that most interstitial macrophages originated from blood monocytes. To define the actions of these cells in PH in vivo, we reduced blood monocyte numbers via genetic deficiency of or in chronically hypoxic male mice and by pharmacologic inhibition of Cxcl1 in monocrotaline-exposed rats. Both models exhibited decreased inflammatory blood monocytes, as well as interstitial macrophages, leading to a substantial decrease in arteriolar remodeling but with a less robust hemodynamic effect. This study defines a direct mechanism by which interstitial macrophages expand in PH. It also demonstrates a pathway for pulmonary vascular remodeling in PH that depends upon interstitial macrophage-dependent inflammation yet is dissociated, at least in part, from hemodynamic consequences, thus offering guidance on future anti-inflammatory therapeutic strategies in this disease.

Neutralization of CXCL12 attenuates established pulmonary hypertension in rats

“…3E) and reduce numbers of macrophages in lungs from MCT-injected and SuHx rats. Remarkably, macrophages have been implicated in the pathogenesis of PAH [34][35][36][37] . This mode of action that allow the blockade of CXCL12 without any effect on the two receptors favors cell homeostasis and the fact that these molecules influence several mechanisms involved in PAH pathobiology are particularly promising in this context.…”

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

“…In PH, patients' expression of chemokines, such CCL1, CCL2, CCL5 and CX3CL1, was increased in circulatory monocytes, along with increased pulmonary levels of CCl1, CCL2, CCL3, CLL3 and CX3CL1 [31]. In CX3CR1 (receptor for CX3CL1)-deficient mice, both pulmonary inflammation and vascular remodeling were reduced after exposure to hypoxia when compared to control mice [31]. Interestingly, in pulmonary vascular endothelial cells from PAH patients, excessive expression of CCL2 was observed, which acts as a chemoattractant for circulating inflammatory cells and as a growth factor for pulmonary arterial smooth muscle cells (PASMCs).…”

“…They might be involved in PH development through their production of cytokines [28][29][30]. Furthermore, the macrophages present in lung perivascular spaces in PAH are derived from peripheral blood monocytes [31], likely indicating their recruitment and differentiation due to pulmonary inflammation. However, chemokines, such as chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X3-C motif) ligand 1 (CX3CL1) monocytes are recruited to the site of the inflammation and differentiate into inflammatory macrophages.…”

“…However, chemokines, such as chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X3-C motif) ligand 1 (CX3CL1) monocytes are recruited to the site of the inflammation and differentiate into inflammatory macrophages. In PH, patients' expression of chemokines, such CCL1, CCL2, CCL5 and CX3CL1, was increased in circulatory monocytes, along with increased pulmonary levels of CCl1, CCL2, CCL3, CLL3 and CX3CL1 [31]. In CX3CR1 (receptor for CX3CL1)-deficient mice, both pulmonary inflammation and vascular remodeling were reduced after exposure to hypoxia when compared to control mice [31].…”

Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension?

“…The pharmacological or genetic ablation of such chemokines and their receptors have been relevant to the pathogenesis of PH [ 3 , 37 ]. Recently, Florentin and colleagues investigated the role and mobilization of blood-borne circulating monocytes and their contribution to arteriolar wall remodeling [ 38 ]. They showed that genetic or pharmacological deficiency of C-X3-C motif chemokine receptor 1 (Cx3cr1)-expressing monocytes limited the recruitment of monocytes and the development of lung remodeling in hypoxia- and monocrotaline (MCT)-induced PH without amelioration of vascular hemodynamics [ 38 ].…”