Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

Ananda S. Mirchandani; 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 Spanos; Kathryn 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

doi:10.1101/2022.03.11.483935

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 language	English
Place of Publication	Cold Spring Harbour Laboratory
Publisher	BioRxiv
Number of pages	53
DOIs	https://doi.org/10.1101/2022.03.11.483935
Publication status	Published - 12 Mar 2022

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2022.03.11.483935v1.fullFinal published version, 1.57 MBLicence: CC BY-NC-ND

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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., ... Walmsley, S. R. (2022). Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence. BioRxiv. https://doi.org/10.1101/2022.03.11.483935

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title = "Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence",

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.",

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

note = "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. This work was funded by a Wellcome Trust Senior Clinical fellowship awarded to S.R.W. (098516 and 209220), Wellcome Trust Post-doctoral Training Clinical Fellowship (110086) and a Wellcome Trust iTPA grant (PIII052) awarded to A.S.M. and was partly funded by UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC). C.C.B holds a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 206234/Z/17/Z).",

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doi = "10.1101/2022.03.11.483935",

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Mirchandani, AS, Jenkins, SJ, Bain, CC, Lawson, H, Coelho, P, Murphy, F, Griffith, D, Zhang, A, Sanchez-Garcia, MA, Reyes, L, Morrison, T, Arienti, S, Sadiku, P, Watts, ER, Dickinson, RS, Clark, S, Ly, T, Lewis, D, Kelly, V, Spanos, C, Musgrave, KM, Delaney, L, Harper, I, Scott, J, Parkinson, NJ, Rostron, AJ, Baillie, KJ, Clohisey, S, Pridans, C, Campana, L, Starkey-Lewis, P, Simpson, AJ, Dockrell, D, Schwarze, J, Hirani, N, Ratcliffe, PJ, Pugh, CW, Kranc, K, Forbes, SJ, Whyte, MK & Walmsley, SR 2022 'Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence' BioRxiv, Cold Spring Harbour Laboratory. https://doi.org/10.1101/2022.03.11.483935

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AU - Murphy, Fiona

AU - Griffith, David

AU - Zhang, Ailiang

AU - Sanchez-Garcia, Manuel A.

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AU - Morrison, Tyler

AU - Arienti, Simone

AU - Sadiku, Pranvera

AU - Watts, Emily R.

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AU - Lewis, David

AU - Kelly, Van

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AU - Musgrave, Kathryn M.

AU - Delaney, Liam

AU - Harper, Isla

AU - Scott, Jonathan

AU - Parkinson, Nicholas J.

AU - Rostron, Anthony J.

AU - Baillie, Kenneth J.

AU - Clohisey, Sara

AU - Pridans, Clare

AU - Campana, Lara

AU - Starkey-Lewis, Philip

AU - Simpson, A. John

AU - Dockrell, David

AU - Schwarze, Jurgen

AU - Hirani, Nikhil

AU - Ratcliffe, Peter J.

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AU - Kranc, Kamil

AU - Forbes, Stuart J.

AU - Whyte, Moira K.

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N1 - The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. This work was funded by a Wellcome Trust Senior Clinical fellowship awarded to S.R.W. (098516 and 209220), Wellcome Trust Post-doctoral Training Clinical Fellowship (110086) and a Wellcome Trust iTPA grant (PIII052) awarded to A.S.M. and was partly funded by UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC). C.C.B holds a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 206234/Z/17/Z).

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N2 - 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.

AB - 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.

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DO - 10.1101/2022.03.11.483935

M3 - Preprint

BT - Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

PB - BioRxiv

CY - Cold Spring Harbour Laboratory

ER -

Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

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