Hoagland, D.A., Rodríguez-Morales, P., Mann, A.O., Yu, S., Lai, A., Baez Vazquez, A., Pope, S.D., Lim, J., Li, S., Zhang, X., Li, M.O., Medzhitov, R., Franklin, R.A. 2023. Macrophages control pathological interferon responses during viral respiratory infection. bioRxiv. DOI:10.1101/2023.12.16.572019


Antiviral immune mediators, including interferons and their downstream effectors, are critical for host defense yet can become detrimental when uncontrolled. Here, we identify a macrophage-mediated anti-inflammatory mechanism that limits type I interferon (IFN-I) responses. Specifically, we found that cellular stress and pathogen recognition induce Oncostatin M (OSM) production by macrophages. OSM-deficient mice succumbed to challenge with influenza or a viral mimic due to heightened IFN-I activation. Macrophage-derived OSM restricted excessive IFN-I production by lung epithelial cells following viral stimulation. Furthermore, reconstitution of OSM in the respiratory tract was sufficient to protect mice lacking macrophage-derived OSM against morbidity, indicating the importance of local OSM production. This work reveals a host strategy to dampen inflammation in the lung through the negative regulation of IFN-I by macrophages.
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