Abstract
CD14+ monocytes contain precursors for macrophages and fibrocytes, known to be involved in regulating airway remodeling in human asthma and distinguishable by the PM-2K marker. We sought to identify circulating subsets of PM-2K+ macrophage-like cells and evaluate their relationships to lung function, severity and control status. Circulating PM-2K+ macrophage-like cells and fibrocytes could be identified and distinguished between normal individuals (N = 152) and asthmatic subjects (N = 133) using multi-parametric flow cytometry. PM-2K+ macrophage-like cells were found to be significantly lower in asthmatic subjects, particularly noted for the CD14−PM-2K+ subset and PM-2K+CCR7−CD86+ cells in subjects with poor lung function (FEV%/FVC% < 80%) as compared to those of normal subjects and asthmatics with normal lung function, whereas the frequency of fibrocytes was higher in asthmatics and the CCR7−CD86+ subset distribution was significantly different in subjects with varying severity. Moreover, exogenous transforming growth factor beta 1 (TGF-β1) was found to inhibit the generation of PM-2K+ macrophage-like cells, but promote the growth of fibrocytes, from CD14+ monocytes, and monocyte-derived TGF-β1 was found to correlate with the lung function, severity and control status in asthmatic patients. Collectively, aberrant differentiation of monocytes into PM-2K+ macrophage-like cell subsets and fibrocytes, together with increased monocyte-derived TGF-β1, characterized patients with severe asthma.
Highlights
Asthma, a common and often debilitating disease, still remains a critical public health, medical and economical problem, for the severe and persistent cases, where airway flow obstruction is often irreversible and is frequently not well controlled by intensive guideline-based therapy[1]
As PM-2K marker has been used to differentiate in vitro monocyte-derived macrophages from fibrocytes[12], we investigated whether circulating PM-2K+ cells and fibrocytes could be identified in the peripheral blood using a multi-color flow cytometry
While the molecular nature of the PM-2K marker remains to be elucidated, it has been used to distinguish the macrophage population in lung tissue[13], in peripheral blood mononuclear cells (PBMCs) from Kawasaki disease[15], and derived from monocyte in vitro[12]
Summary
A common and often debilitating disease, still remains a critical public health, medical and economical problem, for the severe and persistent cases, where airway flow obstruction is often irreversible and is frequently not well controlled by intensive guideline-based therapy[1]. The relative roles of macrophages and fibrocytes in asthma remain to be studied due to the lack of specific markers in these two heterogeneous populations[11]. In the standard conditions of the culture of human macrophages, PM-2K is an established marker to identify macrophages and distinguish macrophages from fibrocytes in monocyte-derived cell populations[12]. This study presents a novel finding that as compared to those in healthy controls, significantly lower frequency of circulating PM-2K+ macrophage-like cell subsets, but higher level of fibrocytes, was noted in subjects with asthma, which was associated with elevated monocyte-derived TGF-β1, correlating with severity and poor lung function
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