Shaping of the alveolar landscape by respiratory infections and long-term consequences for lung immunity

Abstract

Respiratory infections and especially viral infections, along with other extrinsic environmental factors, have been shown to profoundly affect macrophage populations in the lung. In particular, alveolar macrophages (AMs) are important sentinels during respiratory infections and their disappearance opens a niche for recruited monocytes (MOs) to differentiate into resident macrophages. Although this topic is still the focus of intense debate, the phenotype and function of AMs that recolonize the niche after an inflammatory insult, such as an infection, appear to be dictated in part by their origin, but also by local and/or systemic changes that may be imprinted at the epigenetic level. Phenotypic alterations following respiratory infections have the potential to shape lung immunity for the long-term, leading to beneficial responses such as protection against allergic airway inflammation or against other infections, but also to detrimental responses when associated with the development of immunopathologies. This review reports the persistence of virus-induced functional alterations in lung macrophages, and discusses the importance of this imprinting in explaining inter-individual and lifetime immune variation.

Physiological and immunological barriers in the lung

“…Alveolar macrophages (AMs) are the most abundant immune cells in the airway lumen and are crucial components of the respiratory innate immune systems [ 102 ]. They express the high levels of CD11c, Siglec-F, and CD169 and lack CD11b [ 103 ]. GM-CSF is required for the differentiation and maturation of AMs.…”

“…Interstitial macrophages (IMs) are a distinct population of macrophages located in the lung interstitium or parenchyma. They express high levels of CD11b but lack Siglec-F, which distinguishes them from AMs [ 103 ]. While they also have phagocytic functions, IMs are more involved in modulating immune responses and tissue repair.…”

Recruited atypical Ly6G + macrophages license alveolar regeneration after lung injury

“…When not appropriately regulated, they are also thought to contribute to uncontrolled inflammation via the aberrant release of cytokines, which, in its extreme form, is known as a "cytokine storm, " which has been well described in patients with severe COVID-19 (3,(6)(7)(8)(9). Recruited monocytes can also differentiate into monocyte-derived macrophages (Mo-Macs) that are short lived or can establish long-term residency in particular niches and can have functional consequences for lung immunity (10)(11)(12)(13)(14)(15). The idea that recruited Mo-Macs are considered pathogenic after influenza infection (15,16) or COVID-19 (6,17) whereas lung-resident alveolar macrophages (AMs) and interstitial macrophages (IMs) exert beneficial roles (13,(18)(19)(20)(21)(22)(23)(24) is likely oversimplistic.…”