Blocking the human common beta subunit of the GM-CSF, IL-5 and IL-3 receptors markedly reduces hyperinflammation in ARDS models

• Published in: Cell death & disease 2022-02, Vol.13 (2), p.137-137, Article 137
• Main Authors: Wang, Hao, Tumes, Damon J., Hercus, Timothy R., Yip, K. H., Aloe, Christian, Vlahos, Ross, Lopez, Angel F., Wilson, Nick, Owczarek, Catherine M., Bozinovski, Steven
• Format: Article
• Language: English
• Subjects: 631/250/256/2516; 64/60; 692/420/2780/262; 82/1; 96/21; Animals; Antibodies; Antibodies, Monoclonal - immunology; Binding sites; Biochemistry; Biomedical and Life Sciences; Bronchopulmonary infection; Cell Biology; Cell Culture; Colony-stimulating factor; COVID-19; Cytokine Receptor Common beta Subunit - genetics; Cytokine Receptor Common beta Subunit - immunology; Cytokine Receptor Common beta Subunit - physiology; Cytokines; Edema; Eosinophils - immunology; Female; Granulocyte-macrophage colony-stimulating factor; Humans; Immune clearance; Immunity - genetics; Immunity - physiology; Immunology; Inflammation; Inflammation - immunology; Influenza; Influenza A; Interferon; Interleukin 3; Interleukin 5; Leukocytes (eosinophilic); Leukocytes (granulocytic); Leukocytes (neutrophilic); Leukocytes - metabolism; Life Sciences; Lipopolysaccharides; Lungs; Lymphocytes T; Macrophages; Male; Mice; Mice, Transgenic; Monoclonal antibodies; Monocytes; Myeloid cells; Natural killer cells; Neutrophils - metabolism; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Receptors, Interleukin-3; Receptors, Interleukin-5; Respiratory distress syndrome; Respiratory Distress Syndrome - immunology; Respiratory Distress Syndrome - physiopathology; Sepsis; Severe acute respiratory syndrome coronavirus 2; Trauma
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04589-z

Acute respiratory distress syndrome (ARDS) is triggered by various aetiological factors such as trauma, sepsis and respiratory viruses including SARS-CoV-2 and influenza A virus. Immune profiling of severe COVID-19 patients has identified a complex pattern of cytokines including granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-5, which are significant mediators of viral-induced hyperinflammation. This strong response has prompted the development of therapies that block GM-CSF and other cytokines individually to limit inflammation related pathology. The common cytokine binding site of the human common beta (β c ) receptor signals for three inflammatory cytokines: GM-CSF, IL-5 and IL-3. In this study, β c was targeted with the monoclonal antibody (mAb) CSL311 in engineered mice devoid of mouse β c and β IL-3 and expressing human β c (hβ c Tg mice). Direct pulmonary administration of lipopolysaccharide (LPS) caused ARDS-like lung injury, and CSL311 markedly reduced lung inflammation and oedema, resulting in improved oxygen saturation levels in hβ c Tg mice. In a separate model, influenza (HKx31) lung infection caused viral pneumonia associated with a large influx of myeloid cells into the lungs of hβ c Tg mice. The therapeutic application of CSL311 potently decreased accumulation of monocytes/macrophages, neutrophils, and eosinophils without altering lung viral loads. Furthermore, CSL311 treatment did not limit the viral-induced expansion of NK and NKT cells, or the tissue expression of type I/II/III interferons needed for efficient viral clearance. Simultaneously blocking GM-CSF, IL-5 and IL-3 signalling with CSL311 may represent an improved and clinically applicable strategy to reducing hyperinflammation in the ARDS setting.