Myeloid-derived Suppressor Cells Are Necessary for Development of Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) complicates the care of patients with chronic lung disease, such as idiopathic pulmonary fibrosis (IPF), resulting in a significant increase in morbidity and mortality. Disease pathogenesis is orchestrated by unidentified myeloid-derived cells. We used murine models of PH and pulmonary fibrosis to study the role of circulating myeloid cells in disease pathogenesis and prevention. We administered clodronate liposomes to bleomycin-treated wild-type mice to induce pulmonary fibrosis and PH with a resulting increase in circulating bone marrow-derived cells. We discovered that a population of C-X-C motif chemokine receptor (CXCR) 2 myeloid-derived suppressor cells (MDSCs), granulocytic subset (G-MDSC), is associated with severe PH in mice. Pulmonary pressures worsened despite improvement in bleomycin-induced pulmonary fibrosis. PH was attenuated by CXCR2 inhibition, with antagonist SB 225002, through decreasing G-MDSC recruitment to the lung. Molecular and cellular analysis of clinical patient samples confirmed a role for elevated MDSCs in IPF and IPF with PH. These data show that MDSCs play a key role in PH pathogenesis and that G-MDSC trafficking to the lung, through chemokine receptor CXCR2, increases development of PH in multiple murine models. Furthermore, we demonstrate pathology similar to the preclinical models in IPF with lung and blood samples from patients with PH, suggesting a potential role for CXCR2 inhibitor use in this patient population. These findings are significant, as there are currently no approved disease-specific therapies for patients with PH complicating IPF.

Vascular Endothelial Cell-Specific Connective Tissue Growth Factor (CTGF) Is Necessary for Development of Chronic Hypoxia-Induced Pulmonary Hypertension

“…The fact that these non-endothelial cells express CTGF may explain, in part, our findings that after chronic intraperitoneal bleomycin exposure alone (twice weekly for 33 days), eCTGF KO mice were not protected against development of PH (Figure 5B ), or pulmonary fibrosis (Supplementary Figure 1 ). Intriguingly, our group has recently described a novel model for PH, administering bleomycin in combination with clodronate (CL 2 MDP, in figures) liposomes, resulting in depletion of macrophages and robust PH, with nearly no evidence of pulmonary fibrosis (Bryant et al, 2017 ). In light of these findings, we hypothesized that depletion of lung phagocytes with clodronate liposome administration would lead to decreased whole lung CTGF-expression, with a greater dependence on CTGF from the vascular/endothelial compartment in maintaining the wound regulatory balance.…”

“…Furthermore, CTGF expression is sufficient to induce bone marrow mesenchymal stem cells/stromal cells to differentiate into collagen-producing fibroblasts, contributing to fibrogenesis and pathological fibrosis (Lee et al, 2010 ). Interestingly, our group has recently described a contributory role of a similarly immature CD11b + myeloid cell population in vascular remodeling necessary for development of chronic hypoxia-induced PH (Bryant et al, 2017 ). A next step in parsing out the mechanistic pathway leading to disease, will involve exploring the CTGF/CD11b interaction in in vitro and in vivo models, to understand the true molecular effect on pathophysiology of pulmonary vascular remodeling.…”

PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension

“…Additionally, increased expression of endothelial adhesion molecules and proinflammatory cytokines/chemokines, as well as leukocyte recruitment, are also significant features of PH (31,32). Mice deficient in proinflammatory cytokines and endothelial adhesion molecules, as well as those harboring defects in leukocyte recruitment, are not capable of developing severe PH (33)(34)(35). Inflammation, as reflected by the expression levels of proinflammatory cytokines and degree of macrophage infiltration, as well as proliferation of PASMCs, were decreased, along with reduced indices of PH in hypoxic Pfkfb3 +/− mice or 3PO-treated Su/Hx rats.…”

The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis

“…Thus, it is perhaps not surprising that one recent study found that elevated concentrations of peripheral blood MDSCs, defined by the surface markers HLA-DR, CD33, CD11b, CD14, and CD66b, reflect poor lung function in patients with IPF ( 118 ). Another experiment with bleomycin-induced mice showed that MDSCs triggered vascular remodeling and pulmonary hypertension, and that preventing their recruitment via neutralization of CXCR2 normalized the pulmonary pressure ( 119 ). While the relationship between vascular abnormalities and parenchymal fibrosis remains poorly understood, accumulating evidence suggests that these events might significantly impact parenchymal homeostasis during injury and repair ( 45 ).…”