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.

Flow Cytometric Analysis of Macrophages and Dendritic Cell Subsets in the Mouse Lung

“…Lung macrophages consist of two distinct populations, namely, alveolar macrophages that represent longlived tissue-resident macrophages, and short-lived monocytederived interstitial macrophages. Alveolar macrophages play an important role in maintaining lung homeostasis by removing pathogens and noxious particles without inducing inflammation or recruiting monocytes and neutrophils (3,4,27). In contrast, monocyte-derived interstitial macrophages are recruited to the lung from the circulation in response to acute lung injury, and are major contributors to the inflammatory response (3,4,27).…”

“…Alveolar macrophages play an important role in maintaining lung homeostasis by removing pathogens and noxious particles without inducing inflammation or recruiting monocytes and neutrophils (3,4,27). In contrast, monocyte-derived interstitial macrophages are recruited to the lung from the circulation in response to acute lung injury, and are major contributors to the inflammatory response (3,4,27). DCs in the lung are represented by monocyte-derived CD11b 1 DCs, plasmacytoid DCs, and CD103 1 DCs, which originate from distinct precursors and play a crucial role in the induction and suppression of innate immune responses (2, 28).…”

“…1 DCs, and CD11b 1 DCs), play an important role in lung development and physiology, and contribute to important lung diseases, including pulmonary infection, cancer, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis (1)(2)(3)(4)(5). Alveolar and interstitial lung macrophages exhibit different origins and life spans in lungs, and have been identified as key regulators of pathological and reparative processes.…”

The Janus Face of Macrophages in Immunity

“…For example in asthma, recent studies show that M2 macrophages are not just bystanders but also active players in orchestrating allergic lung disease [16]. During chronic obstructive pulmonary disease, macrophage subsets develop in response to cigarette smoke exposure [17]. In tuberculosis, neutrophil extracellular traps binding heat shock protein 72 trigger cytokine release from macrophages.…”

Macrophages: Past, Present and Future

“…The origin and differentiation cues for the subsets of monocytes, tissue macrophages and dendritic cells in mice, and the corresponding cell populations in humans, remain to a large extent unknown [12]. On the other hand, much information is available on other aspects such as the regulation of apoptotic processes by macrophages [13], their role in lymph nodes [9], chronic obstructive pulmonary disease [14] and other pulmonary inflammatory conditions [15] that have been studied extensively. There are also many other mechanisms that we are just beginning to understand.…”