Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

• Published in: bioRxiv
• Main Authors: Mirchandani, Ananda S, Jenkins, Stephen J, Bain, Calum C, Lawson, Hannah, Coelho, Patricia, Murphy, Fiona, Griffith, David, Zhang, Ailiang, Sanchez-Garcia, Manuel A, Reyes, Leila, Morrison, Tyler, Arienti, Simone, Sadiku, Pranvera, Watts, Emily, Dickinson, Rebecca, Clark, Sarah, Ly, Tony, Lewis, David, Kelly, Van, Spanos, Christos, Musgrave, Kathyrn, Delaney, Liam, Harper, Isla, Scott, Jonathan, Parkinson, Nicholas, Rostron, Anthony, Baillie, J Kenneth, Rose Clohisey, Sara Mary, Pridans, Clare, Campana, Lara, Starkey, Philip, Simpson, A John, Dockrell, David, Schwarze, Jurgen, Hirani, Nikhil, Ratcliffe, Peter, Pugh, Christopher, Kranc, Kamil, bes, Stuart, Whyte, Moira, Walmsley, Sarah
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 12.03.2022
• Subjects: Colony-stimulating factor; Hypoxemia; Hypoxia; Inflammation; Interferon; Leukocytes (neutrophilic); Lungs; Macrophages; Monocytes; Phenotypes; Respiratory distress syndrome; Streptococcus infections
• DOI: 10.1101/2022.03.11.483935

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 ARDS. Competing Interest Statement A.S.M, S.R.W, M.K.W, S.J.F, S.J.J have filed a patent for the use of CSF1 as a therapy in ARDS. A.J.S is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the authors and not necessarily those of the NIHR, or the Department of Health and Social Care.