Heterogeneity of lung mononuclear phagocytes in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a disease defined by an aberrant inflammatory response to inhaled cigarette smoke and other noxious particles. The factors triggered in the lungs that drive inflammation and lung tissue destruction are not fully understood, but mononuclear phagocytes play a central role by releasing mediators that promote both inflammation and tissue-destructive emphysema. Although conflicting studies on alveolar macrophages exist regarding chronic cigarette smoke exposure and its effects on macrophage polarization patterns, we have recently identified a cell type in mice defined by CX3CR1 expression. The population of this cell type expands in the lungs and elaborates M1 signature cytokines in response to cigarette smoke exposure in vivo. In addition, the absence of functional CX3CR1 provides protection from tissue-destructive emphysema in a murine model of chronic cigarette smoke exposure. The heterogeneity and plasticity of discrete macrophage subsets, in terms of immunophenotype and function, may explain the seemingly disparate findings showing a suppressed inflammatory profile on the one hand and a heightened inflammatory response on the other. This review examines the evidence that discrete mononuclear phagocyte subsets develop in response to cigarette smoke exposure, and that the spatial cues provided by the lung tissue microenvironment in which the mononuclear phagocytes reside may influence the distribution and function of these subsets.

Fig. 1

Hypothesized role of CX3CR1+ mononuclear phagocytes in COPD. Individuals prone to COPD show a heightened response in the lungs to repetitive cigarette smoking characterized by activation of the transmembrane ligand CX3CL1 (in red). Transmembrane CX3CL1 may transduce a cell survival signal [69,70], or promote adhesive interactions and retention of CX3CR1+ mononuclear phagocytes. The principal cell type producing transmembrane CX3CL1 has still to be identified in human lungs, but the bronchial epithelium [71], airway smooth muscle cells [72,73] and endothelial cells [71,74] have been previously implicated. MMPs such as A disintegrin and metalloproteinase (ADAM)17 or ADAM10 cleave transmembrane CX3CL1 [75,76,77] and the soluble chemokine form of CX3CL1 may promote inflammatory cytokine release, tissue damage and amplify the recruitment of other cell types such as neutrophils or T lymphocytes.