Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

Ananda S. Mirchandani (Lead / Corresponding author), Stephen J. Jenkins, Calum C. Bain, Hannah Lawson, Patricia Coelho, Fiona Murphy, David Griffith, Ailiang Zhang, Manuel A. Sanchez-Garcia, Leila Reyes, Tyler Morrison, Simone Arienti, Pranvera Sadiku, Emily R. Watts, Rebecca S. Dickinson, Sarah Clark, Tony Ly, David Lewis, Van Kelly, Christos SpanosKathryn M. Musgrave, Liam Delaney, Isla Harper, Jonathan Scott, Nicholas J. Parkinson, Anthony J. Rostron, Kenneth J. Baillie, Sara Clohisey, Clare Pridans, Lara Campana, Philip Starkey-Lewis, A. John Simpson, David Dockrell, Jurgen Schwarze, Nikhil Hirani, Peter J. Ratcliffe, Christopher W. Pugh, Kamil Kranc, Stuart J. Forbes, Moira K. Whyte, Sarah R. Walmsley

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Abstract

Acute Respiratory Distress Syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, has no cure. Hypoxemia is a defining feature, yet its impact on inflammation is often neglected. Patients with ARDS are monocytopenic early in the onset of the disease. Endotoxin or Streptococcus pneumoniae acute lung injury (ALI) in the context of hypoxia replicates this finding, through hypoxia-driven suppression of type I interferon signalling. This results in failed lung monocyte-derived interstitial macrophages (IM) niche expansion and unchecked neutrophilic inflammation. Administration of colony stimulating factor 1 (CSF1) rescues the monocytopenia, alters the circulating classical monocyte phenotype in hypoxic endotoxin-driven ALI and enables lung IM population expansion, thus limiting lung injury in endotoxin- and virally-induced hypoxic ALI. Hypoxia directly alters immune dynamics to the detriment of the host and manipulation of this aberrant response offers new therapeutic strategies for A RDS.
Original languageEnglish
Place of PublicationCold Spring Harbour Laboratory
PublisherBioRxiv
Number of pages53
DOIs
Publication statusPublished - 12 Mar 2022

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  • Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation

    Mirchandani, A. S., Jenkins, S. J., Bain, C. C., Sanchez-Garcia, M. A., Lawson, H., Coelho, P., Murphy, F., Griffith, D. M., Zhang, A., Morrison, T., Ly, T., Arienti, S., Sadiku, P., Watts, E. R., Dickinson, R. S., Reyes, L., Cooper, G., Clark, S., Lewis, D., Kelly, V., & 22 othersSpanos, C., Musgrave, K. M., Delaney, L., Harper, I., Scott, J., Parkinson, N. J., Rostron, A. J., Baillie, J. K., Clohisey, S., Pridans, C., Campana, L., Lewis, P. S., Simpson, A. J., Dockrell, D. H., Schwarze, J., Hirani, N., Ratcliffe, P. J., Pugh, C. W., Kranc, K., Forbes, S. J., Whyte, M. K. B. & Walmsley, S. R., Jun 2022, In: Nature Immunology. 23, p. 927-939 13 p.

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