GPR183 antagonism reduces macrophage infiltration in influenza and SARS-CoV-2 infection.

Autor:	Foo CX; Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia.; Contributed equally to this work., Bartlett S; Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia.; Contributed equally to this work., Chew KY; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia., Ngo MD; Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia., Bielefeldt-Ohmann H; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia., Arachchige BJ; Centre for Clinical Research, The University of Queensland, Brisbane, Australia., Matthews B; Centre for Clinical Research, The University of Queensland, Brisbane, Australia., Reed S; Centre for Clinical Research, The University of Queensland, Brisbane, Australia., Wang R; Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia., Smith C; Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia., Sweet MJ; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia.; Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Australia., Burr L; Dept of Respiratory Medicine, Mater Adult Hospital, Brisbane, Australia., Bisht K; Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia., Shatunova S; Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia., Sinclair JE; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia., Parry R; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia., Yang Y; Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia., Lévesque JP; Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia., Khromykh A; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia., Rosenkilde MM; Dept of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Short KR; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia., Ronacher K; Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia katharina.ronacher@mater.uq.edu.au.; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2023 Mar 09; Vol. 61 (3). Date of Electronic Publication: 2023 Mar 09 (Print Publication: 2023).
DOI:	10.1183/13993003.01306-2022
Abstrakt:	Rationale: Severe viral respiratory infections are often characterised by extensive myeloid cell infiltration and activation and persistent lung tissue injury. However, the immunological mechanisms driving excessive inflammation in the lung remain poorly understood. Objectives: To identify the mechanisms that drive immune cell recruitment in the lung during viral respiratory infections and identify novel drug targets to reduce inflammation and disease severity. Methods: Preclinical murine models of influenza A virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Results: Oxidised cholesterols and the oxysterol-sensing receptor GPR183 were identified as drivers of monocyte/macrophage infiltration to the lung during influenza A virus (IAV) and SARS-CoV-2 infection. Both IAV and SARS-CoV-2 infection upregulated the enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) in the lung, resulting in local production of the oxidised cholesterols 25-hydroxycholesterol (25-OHC) and 7α,25-dihydroxycholesterol (7α,25-OHC). Loss-of-function mutation of Gpr183 or treatment with a GPR183 antagonist reduced macrophage infiltration and inflammatory cytokine production in the lungs of IAV- or SARS-CoV-2-infected mice. The GPR183 antagonist significantly attenuated the severity of SARS-CoV-2 infection and viral loads. Analysis of single-cell RNA-sequencing data on bronchoalveolar lavage samples from healthy controls and COVID-19 patients with moderate and severe disease revealed that CH25H , CYP7B1 and GPR183 are significantly upregulated in macrophages during COVID-19. Conclusion: This study demonstrates that oxysterols drive inflammation in the lung via GPR183 and provides the first preclinical evidence for the therapeutic benefit of targeting GPR183 during severe viral respiratory infections. Competing Interests: Conflict of interest: S. Bartlett reports an early career seed grant from the Mater Foundation, supporting the present study. H. Bielefeldt-Ohmann reports consulting fees from Paradigm Biopharma, Queensland University of Technology and Colorado State University, outside the submitted work. M.J. Sweet reports grants from National Health and Medical Research Council of Australia, outside the submitted work. K. Bisht reports grants from the American Society of Hematology (ASH) Global Research Award, and Translational Research Institute-Mater Research LINC grant, Mater Foundation, outside the submitted work. Y. Yang reports grants from Mater Foundation, supporting the present study. J-P. Lévesque reports grants from National Health and Medical Research Council, and US Department of Defense; and royalties or licences from GlycoMimetics Inc., outside the submitted work. M.M. Rosenkilde reports support for the animal studies and breeding in Denmark of the mouse strain used in this study from Independent Research Fund Denmark; grants from Independent Research Fund Denmark, Novo Nordisk Foundation; donations from deceased Valter Alex Torbjørn Eichmuller (VAT Eichmuller)-2020-117043, and Kirsten and Freddy Johansens Foundation (KFJ) - 2017-112697; royalties from Antag Therapeutics and Bainan Biotech from patents made at the University of Copenhagen; travel support from Gordon Research Conference 2022; and is the co-founder of the following biotech companies: Antag Therapeutics, Bainan Biotech, Synklino, outside the submitted work. K.R. Short reports grants from National Health and Medical Research Council of Australia; and consulting fees from Sanofi, Novo Nordisk and Roche, outside the submitted work. K. Ronacher reports support for the present manuscript from Mater Foundation, Diabetes Australia, Australian Infectious Diseases Research Centre, Australian Respiratory Council; and grants from NIH R01 (5R01AI116039), outside the submitted work. All other authors have nothing to disclose. (Copyright ©The authors 2023.)
Databáze:	MEDLINE
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