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Scientists have identified a novel group of immune cells in the lungs that are associated with the control of inflammation during viral infections, like influenza or possibly coronavirus. This discovery may help to advance the development of therapeutics to treat inflammation-related lung conditions such as bronchitis, influenza and potentially even COVID-19.



Macrophages are an important subset of phagocytic immune cells found throughout the body that form part of our body’s first line of defense against invading foreign material, including bacteria and viruses. Alveolar macrophages (AMs) are a well-known inhabitant of the lungs and are responsible for direct clearance of viruses. This new group of immune cells, identified in the lungs of mice, are a distinct group of macrophages, dubbed NAMs (nerve and airway associated macrophages), that appear instead to moderate inflammation in the lungs during viral infection. Inflammation is an important part of the innate immune response to potentially harmful foreign material and includes the production of regulatory molecules, such as cytokines, and recruitment of immune cells to the affected locations. If inflammation goes unchecked, however, it can be damaging to the body and therefore requires tight regulation.



The study was published today in Science Immunology.



The team, including scientists Columbia University Medical Center, New York University Langone Health, Uconn Health and the University of Bordeaux, studied the location and role of these novel immune cells. Professor Kamal M. Khanna, corresponding author of the paper, commented “Emerging evidence suggests that tissue-resident macrophages play critical roles in maintaining immune and tissue homeostasis in mucosal organs under inflammatory conditions, such as during infections. Although studies primarily using bone marrow-derived macrophages have been very informative about the function of macrophages in response to specific stimuli in vitro, these roles remain to be elucidated among tissue-resident macrophage subsets in the context of infection in the local tissue environment in vivo. This was one of the main goals of our study.”



Using live cell imaging in live mice, they found that NAMs cluster primarily around the sympathetic pulmonary nerves and airways. With the use of mouse models unable to produce either AMs or NAMs, they were able to demonstrate that NAMs were embryonically derived, self-renewing, and altogether developmentally distinct from AMs. Unlike AMs, the development of NAMs requires colony-stimulating factor 1 (CSF1) but not granulocyte-macrophage CSF (GM-CSF) on which AM development and maturation is highly dependent.



Population and single cell transcriptome analysis revealed that NAMs were distinct from other macrophage groups resident in the lungs at the transcriptional level too. The analysis also indicated that NAMs highly transcribed immunoregulatory genes under steady-state and inflammatory conditions. “I think what excites me most about our findings is the fact that we have identified a unique subset of the macrophage population (a critical cell type of the innate immune system) that we know very little about. Our results provide essential insights into the development and maintenance, and functions of a poorly understood subset of resident macrophages in the lung” said Professor Khanna.



Mice were experimentally infected with influenza virus to examine the role of NAMs during infection. This revealed that NAMs proliferated robustly following infection in the wild-type mice. However, in those unable to produce NAMs, infection induced an overzealous immune response with excessive production of inflammatory cytokines and immune cell infiltration into tissues. “We find that, at least with influenza, AMs help clear the infection, while NAMs help regulate and suppress infection-induced inflammation”. This transcriptionally and developmentally distinct subset of airway-associated macrophages are therefore important in maintaining immune and tissue homeostasis, information that provides insights for future therapeutic developments, including those against COVID-19.



“As we come to understand more about how NAMs regulate infection-induced inflammation we can target these macrophages to help resolve damaging inflammation caused by respiratory viral infections such as COVID-19.” He concluded “Future studies will examine how to augment their function or induce their proliferation to increase their numbers at the right time during viral infections”.



Reference

Identification of a nerve-associated, lung-resident interstitial macrophage subset with distinct localization and immunoregulatory properties. Basak B. Ural, Stephen T. Yeung, Payal Damani-Yokota, Joseph C. Devlin, Maren de Vries, Paola Vera-Licon, Tasleem Samji, Catherine M. Sawai, Geunhyo Jang, Oriana A. Perez, Quynh Pham, Leigh Maher, P'ng Loke, Meike Dittmann, Boris Reizis, Kamal M. Khanna. Sci. Immunol. 5, eaax8756 (2020), 10.1126/sciimmunol.aax8756.



