Role of resident macrophages in type II responses and trained immunity

New York University School Of Medicine, New York NY

Investigators

Abstract

ABSTRACT The importance of tissue resident macrophages for pathogen clearance and tissue homeostasis is beginning to emerge. However, our understanding of the multifaceted roles these macrophages play in mucosal tissues such as the lung remains incomplete. The lung is a very complex organ with specialized structures to allow for adequate gas exchange. The pulmonary microenvironment is unique and has a direct and important influence on the resident immune cells, especially macrophage populations. One of the most important function of macrophages is to regulate type 2 inflammatory pathways during helminth infections and allow for the resolution inflammation and tissue damage after the pathogen is cleared. The precise cellular and molecular mechanisms that macrophage populations utilize to accomplish these critical functions in vivo are not well understood. We recently reported the discovery of an interstitial subset of CD169+ lung-resident macrophages that are transcriptionally and developmentally distinct from alveolar macrophages (AMs). These CD169+ interstitial macrophages (IM) are primarily localized around the large airways in mice and humans and in close proximity to the nerves in the bronchovascular bundle. Our work has shown that these nerve- and airway-associated macrophages (NAMs) are tissue resident, and express high levels of immunoregulatory genes that are strongly associated with type 2 immune responses under steady-state and inflammatory conditions. Nevertheless, the role of NAMs in regulating type 2 immune responses is not well understood. Using the Nippostrongylus brasiliensis (Nb) model our preliminary data shows that NAMs are critical for mediating type 2 immune responses and tissue repair following infection. Furthermore, we have observed that NAMs in particular continue to increase in numbers long after Nb is cleared, which suggests this macrophage subset may exhibit epigenetic changes reflective of an important role in mediating trained immunity. Indeed, our studies show that as late as 6 weeks after Nb infection mice exhibit remarkable protection from subsequent respiratory viral infections. Thus, the overarching hypothesis to be tested in this proposal is that lung resident macrophage subsets, (in particular NAMs) carry out distinct functions, and their unique positioning and remarkable gene expression profile make them critically important for regulating type 2 immune responses and tissue homeostasis. Furthermore, in response to pathogens that trigger a robust type 2 immune response lung resident macrophages exhibit hallmarks of trained immunity that have important consequences for subsequent heterologous infections.