Abundance of Non-Polarized Lung Macrophages with Poor Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD)

Abstract

Lung macrophages are the key immune effector cells in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Several studies have shown an increase in their numbers in bronchoalveolar lavage fluid (BAL) of subjects with COPD compared to controls, suggesting a pathogenic role in disease initiation and progression. Although reduced lung macrophage phagocytic ability has been previously shown in COPD, the relationship between lung macrophages’ phenotypic characteristics and functional properties in COPD is still unclear. (1) Methods: Macrophages harvested from bronchoalveolar lavage (BAL) fluid of subjects with and without COPD (GOLD grades, I–III) were immuno-phenotyped, and their function and gene expression profiles were assessed using targeted assays. (2) Results: BAL macrophages from 18 COPD and 10 (non-COPD) control subjects were evaluated. The majority of macrophages from COPD subjects were non-polarized (negative for both M1 and M2 markers; 77.9%) in contrast to controls (23.9%; p < 0.001). The percentages of these non-polarized macrophages strongly correlated with the severity of COPD (p = 0.006) and current smoking status (p = 0.008). Non-polarized macrophages demonstrated poor phagocytic function in both the control (p = 0.02) and COPD (p < 0.001) subjects. Non-polarized macrophages demonstrated impaired ability to phagocytose Staphylococcus aureus (p < 0.001). They also demonstrated reduced gene expression for CD163, CD40, CCL13 and C1QA&B, which are involved in pathogen recognition and processing and showed an increased gene expression for CXCR4, RAF1, amphiregulin and MAP3K5, which are all involved in promoting the inflammatory response. (3) Conclusions: COPD is associated with an abundance of non-polarized airway macrophages that is related to the severity of COPD. These non-polarized macrophages are predominantly responsible for the poor phagocytic capacity of lung macrophages in COPD, having reduced capacity for pathogen recognition and processing. This could be a key risk factor for COPD exacerbation and could contribute to disease progression.

Hsa-Mir-320c, Hsa-Mir-200c-3p, and Hsa-Mir-449c-5p as Potential Specific miRNA Biomarkers of COPD: A Pilot Study

“…EGFR, a member of the “ErbB signaling pathway”, has also been found to mediate macrophage activation in the pathological context [ 50 , 51 ]. Macrophages are key immune effector cells in the pathogenesis of COPD, and BAL-macrophages from COPD patients have been reported to present a non-polarized phenotype that confers them a poor immune response [ 52 , 53 ]. As the “ErbB signaling pathway” was also detected in our in silico analysis, the three miRNAs candidates might be implicated in the alteration of the EGFR role in macrophage function in COPD.…”

Lung Macrophages: Pivotal Immune Effector Cells Orchestrating Acute and Chronic Lung Diseases

“…Berenson and co-workers showed that macrophages from patients with COPD have impaired phagocytosis of respiratory pathogens which strongly correlated with COPD severity (FEV1% predicted) [63]. Studies from our laboratory recently showed that the majority of airspace macrophages in COPD do not express either M1 or M2 markers and that these "non-polarized" macrophages have significantly reduced phagocytic capacity compared to polarized (M1 or M2) macrophages [30]. In this study, airspace macrophages could be divided into 4 distinct groups using surface markers, as either M1, M2, dual positive for M1 & M2 (double polarized) or negative for both M1 & M2 markers (non-polarized).…”

“…This switch in polarization is dynamic and induced predominantly by their microenvironment. The distinct M1 and M2 subtypes is an overly simplification of macrophage polarization, for example, 5% of the macrophages in lung cancer specimens express both M1 and M2 markers [29], and mixed macrophage polarization have been described in other lung conditions [29,30]. With the advent of genetic analysis and specifically single cell RNA sequencing technology, the basic macrophage characterization of M1 and M2 phenotypes has been challenged and may change in the near future [31].…”

Reduced phagocytic activity of human alveolar macrophages infected with Mycobacterium avium complex

“…Among these cell types, alveolar macrophages provide the first line of defense against extrinsic organisms that reach the alveolar airspace, where distinct macrophage subpopulations exhibit distinct functional properties [14]. Macrophages have been characterized either as "classically" activated or M1 macrophages or "alternatively" activated or M2 macrophages [14,15]; however, macrophages negative for both M1 and M2 markers (non-polarized macrophages) are also reportedly associated with chronic inflammation [16,17]. A higher rate of non-polarized macrophages may account for impaired phagocytic activity and is associated with disease severity and progression in patients with chronic obstructive pulmonary disease (COPD) [16].…”