Macrophages-the immune effector guardians of the lung: impact of corticosteroids on their functional responses

Abstract

Lung macrophages (LMs) are key immune effector cells that protect the lung from inhaled particulate matter, noxious gases and pathogens. In Chronic Obstructive Pulmonary Disease (COPD), there is an abundance of macrophages in airspaces and lung tissues suggesting that they play an important role in the pathogenesis of the disease. Furthermore, macrophage phenotype and functional properties are altered in COPD toward a more pro-inflammatory state, characterized by reduced pathogen recognition and processing ability and dysfunctional tissue repair qualities. Inhaled corticosteroids (ICSs), used in the management of COPD, has been shown to reduce acute exacerbations of COPD but is also associated with increased occurrence of pneumonia. Corticosteroids treatment altered LM phenotypic characteristics and their functional properties, and this commentary discusses current knowledge and also the gaps in our understanding of the impact of ICS on LMs phenotype and function. A better understanding of how ICSs impact the immune-inflammatory responses in the lung, in particular ICSs' effects on LMs, could allow more selective personalized tailoring of the use of ICSs in COPD to improve disease progression, morbidity and mortality.

Keywords: COPD; corticosteroids; macrophages.

Figure 1. The impact of noxious gases and particulate matter (CS and ambient air pollutants) on LM phenotype and disease progression in COPD: effect of corticosteroids

Inhaled toxins and particles are processed by airspace macrophages which shift them to a more M1 phenotype with the production of pro-inflammatory mediators including, IL1-β, IL-6, TNF-α which promote the recruitment of polymorphonuclear leukocytes such as neutrophils and eosinophils as well as monocytes into the airspaces to clear these toxins and particulate matter from the airspaces. However, with chronic exposure, resident M1 macrophages and new MDM phagocytic and efferocytosis functions are compromised leading to chronic low-grade inflammation and eventual bacterial colonization of airspaces. This chronic airway inflammation and bacterial colonization are associated with frequent infectious exacerbation that lead to COPD disease progression. M2 macrophages are involved in inflammation resolution, tissue remodeling and repair, but this phenotype and their function are suppressed by the chronic inflammatory insult of inhaled toxins and particulate matter. Corticosteroids exposure (either inhaled or systemic) reduce pro-inflammatory cytokine production by macrophages and shift macrophage phenotype more toward M2 phenotype and function which increase tissue reparative mediators (IL-10 and TGF-β1), increase CD206 expression (to increase pathogen recognition and processing), CD163 (to reduce pathogen survival by scavenging iron ions) and up-regulating MERTK (to enhance cell efferocytosis of apoptotic cells and cell debris). This macrophage phenotype shift will promote resolution of inflammation and tissue repair, reduce bacterial colonization thereby slowing disease progression in COPD.