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

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

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    Abstract

    Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.
    Original languageEnglish
    Pages (from-to)927-939
    Number of pages13
    JournalNature Immunology
    Volume23
    Early online date27 May 2022
    DOIs
    Publication statusPublished - Jun 2022

    Keywords

    • Acute inflammation
    • Haematopoiesis
    • Monocytes and macrophages
    • Mucosal immunology

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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    • Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

      Mirchandani, A. S., Jenkins, S. J., Bain, C. C., Lawson, H., Coelho, P., Murphy, F., Griffith, D., Zhang, A., Sanchez-Garcia, M. A., Reyes, L., Morrison, T., Arienti, S., Sadiku, P., Watts, E. R., Dickinson, R. S., Clark, S., Ly, T., Lewis, D., Kelly, V., Spanos, C., & 21 othersMusgrave, K. M., Delaney, L., Harper, I., Scott, J., Parkinson, N. J., Rostron, A. J., Baillie, K. J., Clohisey, S., Pridans, C., Campana, L., Starkey-Lewis, P., Simpson, A. J., Dockrell, D., Schwarze, J., Hirani, N., Ratcliffe, P. J., Pugh, C. W., Kranc, K., Forbes, S. J., Whyte, M. K. & Walmsley, S. R., 12 Mar 2022, Cold Spring Harbour Laboratory: BioRxiv, 53 p.

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