The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity

Abstract

The last decade has been somewhat of a renaissance period for the field of macrophage biology. This renewed interest, combined with the advent of new technologies and development of novel model systems to assess different facets of macrophage biology, has led to major advances in our understanding of the diverse roles macrophages play in health, inflammation, infection and repair, and the dominance of tissue environments in influencing all of these areas. Here, we discuss recent developments in our understanding of lung macrophage heterogeneity, ontogeny, metabolism and function in the context of health and disease, and highlight core conceptual advances and key unanswered questions that we believe should be focus of work in the coming years.

Fig. 1. Heterogeneity, phenotypic profiles and functions of macrophages in the healthy lung.

The lung macrophage compartment is heterogeneous, with at least two populations occupying distinct anatomical niches in the healthy lung. Macrophages are present in the bronchoalveolar space, including the alveoli where gaseous exchange occurs. Alveolar macrophages (AlvMϕs) are defined by their expression of CD11c, MARCO and CD169 in both mice and humans, although additional species-specific markers must be used to define them accurately. AlvMϕs are crucial for regulating surfactant produced by the respiratory epithelium as well as maintaining epithelial integrity and responsiveness. Their high phagocytic capability allows them to clear apoptotic/senescent cells and inhaled particles efficiently. They also act as the first line of defence against air-borne pathogens, although the relative role of resident AlvMϕs versus elicited, monocyte-derived macrophages in immune protection varies depending on the nature of the insult (see text and Fig. 3). Macrophages are also found in the interstitial space between the alveoli and the capillary beds, as well as surrounding larger airways (bronchi). These interstitial macrophages (IntMϕs) are phenotypically distinct from AlvMϕs and at least two subsets exist in mouse and man defined by differential expression of MHCII (HLA-DR), Lyve-1 and/or CD36. IntMϕs may act as a second line of defence under the epithelial barrier and basement membrane. In health, they may support the stromal/structural compartment through growth factor supply, as well as maintaining T cells and acting a rich source of IL-10. Although nerve- and blood vessel (BV)-associated IntMϕs have been described, whether these represent obligate niches is under debate.

Fig. 2. Pulmonary macrophage ontogeny during health.

The contribution of distinct progenitors to the pulmonary macrophage compartments is highly dynamic and alters with age. During embryonic development (in mice) yolk sac-derived macrophages colonise the lung and these remain present at birth. However, these are outnumbered by foetal liver-derived progenitors that enter the lung prior to birth, some of which move into the airways upon alveolarization within the first days of life. During the neonatal period, where there is massive tissue growth, all macrophages show high levels of proliferation to occupy the newly created niches. This is sufficient to expand the AlvMϕ compartment with little, if any, contribution from bone marrow-derived monocytes. However, recent work has suggested that during adulthood under homeostatic conditions AlvMϕs are replenished, albeit at low rates, by bone marrow-derived, CCR2-dependent monocytes. These monocytes replace IntMϕs at a higher rate, although in the unperturbed lung, the IntMϕ compartment likely contains macrophages derived from the yolk sac, foetal liver and bone marrow, with the latter dominating numerically.

Fig. 3. Pulmonary macrophage dynamics during inflammation and resolution.

In inflammation caused by agents such as pathogens, pollutants or allergens, most resident AlvMϕs are lost and replaced by monocyte-derived Mϕs and perhaps ex-IntMϕs. This occurs in parallel to accumulation of other inflammatory cells such as neutrophils and eosinophils, recruitment of which to the airways is facilitated by chemokines and disrupted barrier integrity. During resolution of the damage caused by acute inflammation, and/or in the face of chronic low-level inflammation, residual AlvMϕs can self-renew through proliferation, clear up dying or dysfunctional cells in the airways, as well as be replenished through conversion of monocyte-derived macrophages and ex-IntMϕs which are transcriptionally, epigenetically and functionally conditioned by the airway environment to take on AlvMϕ identity.