Loss of GM-CSF-dependent Instruction of Alveolar Macrophages in COVID-19 Provides a Rationale for Inhaled GM-CSF Treatment

GM-CSF promotes myelopoiesis and inflammation, and GM-CSF blockade is being evaluated as a treatment for COVID-19-associated hyperinflammation. Alveolar GM-CSF is, however, required for monocytes to differentiate into alveolar macrophages (AMs) that control alveolar homeostasis. By mapping cross-species AM development to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of pro-inflammatory macrophages. In a multi-center, open-label RCT in 81 non-ventilated COVID-19 patients with respiratory failure, we found that inhalation of rhu-GM-CSF did not improve mean oxygenation parameters compared with standard treatment. However, more patients on GM-CSF had a clinical response, and GM-CSF inhalation induced higher numbers of virus-specific CD8 effector lymphocytes and class-switched B cells, without exacerbating systemic hyperinflammation. This translational proof-of-concept study provides a rationale for further testing of inhaled GM-CSF as a non-invasive treatment to improve alveolar gas exchange and simultaneously boost antiviral immunity in COVID-19. This study is registered at ClinicalTrials.gov (NCT04326920) and EudraCT (2020-001254-22).

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References

. Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci Immunol. 2021; 6(59). PMC: 8158979. DOI: 10.1126/sciimmunol.abh2259. View

Merad M, Martin J . Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020; 20(6):355-362. PMC: 7201395. DOI: 10.1038/s41577-020-0331-4. View

Mehta P, Porter J, Manson J, Isaacs J, Openshaw P, McInnes I . Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities. Lancet Respir Med. 2020; 8(8):822-830. PMC: 7834476. DOI: 10.1016/S2213-2600(20)30267-8. View

Aegerter H, Lambrecht B, Jakubzick C . Biology of lung macrophages in health and disease. Immunity. 2022; 55(9):1564-1580. PMC: 9533769. DOI: 10.1016/j.immuni.2022.08.010. View

Bost P, Giladi A, Liu Y, Bendjelal Y, Xu G, David E . Host-Viral Infection Maps Reveal Signatures of Severe COVID-19 Patients. Cell. 2020; 181(7):1475-1488.e12. PMC: 7205692. DOI: 10.1016/j.cell.2020.05.006. View

Sterner R, Sakemura R, Cox M, Yang N, Khadka R, Forsman C . GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2018; 133(7):697-709. PMC: 6376281. DOI: 10.1182/blood-2018-10-881722. View

Mehta P, McAuley D, Brown M, Sanchez E, Tattersall R, Manson J . COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395(10229):1033-1034. PMC: 7270045. DOI: 10.1016/S0140-6736(20)30628-0. View

Grifoni A, Sidney J, Vita R, Peters B, Crotty S, Weiskopf D . SARS-CoV-2 human T cell epitopes: Adaptive immune response against COVID-19. Cell Host Microbe. 2021; 29(7):1076-1092. PMC: 8139264. DOI: 10.1016/j.chom.2021.05.010. View

Huang F, Barnes P, Feng Y, Donis R, Chroneos Z, Idell S . GM-CSF in the lung protects against lethal influenza infection. Am J Respir Crit Care Med. 2011; 184(2):259-68. PMC: 6938174. DOI: 10.1164/rccm.201012-2036OC. View

10.

Myhre P, Prebensen C, Strand H, Roysland R, Jonassen C, Rangberg A . Growth Differentiation Factor 15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized With COVID-19. Circulation. 2020; 142(22):2128-2137. PMC: 7688084. DOI: 10.1161/CIRCULATIONAHA.120.050360. View

11.

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

12.

Aegerter H, Kulikauskaite J, Crotta S, Patel H, Kelly G, Hessel E . Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection. Nat Immunol. 2020; 21(2):145-157. PMC: 6983324. DOI: 10.1038/s41590-019-0568-x. View

13.

Mould K, Barthel L, Mohning M, Thomas S, McCubbrey A, Danhorn T . Cell Origin Dictates Programming of Resident versus Recruited Macrophages during Acute Lung Injury. Am J Respir Cell Mol Biol. 2017; 57(3):294-306. PMC: 5625228. DOI: 10.1165/rcmb.2017-0061OC. View

14.

Schneider C, Nobs S, Kurrer M, Rehrauer H, Thiele C, Kopf M . Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat Immunol. 2014; 15(11):1026-37. DOI: 10.1038/ni.3005. View

15.

Sturrock A, Vollbrecht T, Mir-Kasimov M, McManus M, Wilcoxen S, Paine 3rd R . Mechanisms of suppression of alveolar epithelial cell GM-CSF expression in the setting of hyperoxic stress. Am J Physiol Lung Cell Mol Physiol. 2009; 298(3):L446-53. PMC: 2838677. DOI: 10.1152/ajplung.00161.2009. View

16.

Overgaard C, Schlingmann B, Dorsainvil White S, Ward C, Fan X, Swarnakar S . The relative balance of GM-CSF and TGF-β1 regulates lung epithelial barrier function. Am J Physiol Lung Cell Mol Physiol. 2015; 308(12):L1212-23. PMC: 4499033. DOI: 10.1152/ajplung.00042.2014. View

17.

Tazawa R, Ueda T, Abe M, Tatsumi K, Eda R, Kondoh S . Inhaled GM-CSF for Pulmonary Alveolar Proteinosis. N Engl J Med. 2019; 381(10):923-932. DOI: 10.1056/NEJMoa1816216. View

18.

Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C . Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8(4):420-422. PMC: 7164771. DOI: 10.1016/S2213-2600(20)30076-X. View

19.

Rosler B, Herold S . Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy?. Mol Cell Pediatr. 2016; 3(1):29. PMC: 4969252. DOI: 10.1186/s40348-016-0055-5. View

20.

Vanderbeke L, Van Mol P, Van Herck Y, De Smet F, Humblet-Baron S, Martinod K . Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity. Nat Commun. 2021; 12(1):4117. PMC: 8257697. DOI: 10.1038/s41467-021-24360-w. View