Lung Macrophage Functional Properties in Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is caused by the chronic exposure of the lungs to toxic particles and gases. These exposures initiate a persistent innate and adaptive immune inflammatory response in the airways and lung tissues. Lung macrophages (LMs) are key innate immune effector cells that identify, engulf, and destroy pathogens and process inhaled particles, including cigarette smoke and particulate matter (PM), the main environmental triggers for COPD. The number of LMs in lung tissues and airspaces is increased in COPD, suggesting a potential key role for LMs in initiating and perpetuating the chronic inflammatory response that underpins the progressive nature of COPD. The purpose of this brief review is to discuss the origins of LMs, their functional properties (chemotaxis, recruitment, mediator production, phagocytosis and apoptosis) and changes in these properties due to exposure to cigarette smoke, ambient particulate and pathogens, as well as their persistent altered functional properties in subjects with established COPD. We also explore the potential to therapeutically modulate and restore LMs functional properties, to improve impaired immune system, prevent the progression of lung tissue destruction, and improve both morbidity and mortality related to COPD.

Keywords: COPD; function; lung macrophages.

Figure 1

Lung macrophage (LM) phenotypes: LMs consist of at least four broad phenotypes. Non-polarized macrophages are M1 and M2 marker-negative and secrete low levels of cytokines. They become polarized to M1 macrophages due to stimulation by T helper type 1 cell (Th1) cytokines and secrete high levels of pro-inflammatory cytokines. Polarization to M2 macrophages is due to exposure to Th2 cytokines and these M2 macrophages secrete high levels of anti-inflammatory cytokines. “?” The role, functional properties, and forming process of dual-polarized macrophages (M1 and M2 marker-positive) are still unclear.

Figure 2

Apoptosis in lung macrophage is determined by a variety of apoptotic (oxidative stress, Bax, and mitochondrial dysfunction such as cytochrome c release) and anti-apoptotic (p21^CIP1/WAF, Bcl-xL, and MafB) factors. Exposure to cigarette smoke and pathogens impact this balance of anti-apoptotic and apoptotic factors. This could contribute to reduced clearance of dead cell and cell debri augmenting the chronic inflammatory response in lung tissues of chronic obstructive pulmonary disease subjects. Bax: B-cell lymphoma protein 2-associated X; Bcl-xL: B-cell lymphoma-extra large; MafB: v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B.

Figure 3

Lung macrophage (LM) kinetics and phenotypes in chronic obstructive pulmonary disease (COPD): 1. Blood monocyte-derived macrophages (MDMs) migrate into small airways and airspaces and this migration is activated by chemokines such as CCL2 or monocyte chemoattractant protein-1 (MIP-1) [69], CXCL9, CXCL10, CXCL11, and CCL5 (RANTES) [66]. 2. Interstitial macrophages (IMs). MDMs are recruited to the lung interstitium and differentiate into IMs [49]. 3. Non-polarized macrophages. IMs recruited into both small airways and larger airspaces are initially non-polarized and are polarized to either M1 macrophages or M2 macrophages dependent on the microenvironment [12]. 4. M1 macrophages. They secrete pro-inflammatory cytokines such as IL-6, IL-1β and TNF-α [76,77,78,79], which could damage lung tissues if secreted in excess. In COPD, phagocytosis and efferocytosis of microorganisms of M1 macrophages is impaired [24,106,108,109,110,111,112], which may lead to bacterial colonization. 5. M2 macrophages or alternative acitivated macrophages are involved in the resolution of inflammation and tissue repair. In COPD, they produce MMPs (MMP-2, 9, and 12) [52,57] and cathepsins (cathepsins K, L, and S) [58] as proteases and release significantly less of the tissue inhibitor of metalloproteinase (TIMP)-1 as a anti-elastolytic molecule [52,87], which could induce tissues damage and amplify the inflammatory response contributing to tissue destruction. Phagocytosis and efferocytosis of cell debris and apoptotic cells are also impaired [105,113,114,115,116,117,118]. These apoptotic cells which are not eliminated undergo secondary necrosis with further release of inflammatory mediators that decrease efferocytosis, causing a vicious cycle [124]. The chronic inflammatory process further increases during acute exacerbations and is associated with a poor long-term outcome [5].

Figure 4

Therapeutics impacting lung macrophages (LMs). Macrolides increase the phagocytic ability of LMs, which could be related to an increase in mannose receptor expression (CD206) and involve the phosphoserine (PS) pathway [121,122,174]. Statins regulate prenylation of the renin–angiotensin system (Ras) homolog family member (Rho)-guanosine triphosphatases (GTPases) that block 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, decreasing the production of mevalonate and downstream prenylation substrates such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Statins strengthen efferocytosis mediated by RhoA inhibition through GGPP in addition to lowering cholesterol through FPP [198]. Mannose-binding lectin (MBL) increases the phagocytic ability of LMs via the Ras-related C3 botulinum toxin substrate (Rac) 1/2/3 signaling pathway, which mediates actin cytoskeleton rearrangement required for macrophage engulfment of apoptotic cells [186]. T-bar define blocking activity