Samuel Philip Nobs1, Lea Pohlmeier2, Fengqi Li2, Merve Kayhan2, Burkhard Becher3, Manfred Kopf4. 1. Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. 2. Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland. 3. Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. 4. Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland. Electronic address: manfred.kopf@ethz.ch.
Abstract
BACKGROUND: Steroid-resistant asthma is often characterized by high levels of neutrophils and mixed TH2/TH17 immune profiles. Indeed, neutrophils are key drivers of chronic lung inflammation in multiple respiratory diseases. Their numbers correlate strongly with disease severity, and their presence is often associated with exacerbation of chronic lung inflammation. OBJECTIVE: What factors drive development of neutrophil-mediated chronic lung disease remains largely unknown, and we sought to study the role of GM-CSF as a potential regulator in chronic asthma. METHODS: Different experimental animal models of chronic asthma were used in combination with alveolar macrophage-reconstitution of global GM-CSF receptor knockout mice as well as cell-type-specific knockout animals to elucidate the role of GM-CSF signaling in chronic airway inflammation. RESULTS: We identify GM-CSF signaling as a critical factor regulating pulmonary accumulation of neutrophils. We show that although being not required for intrinsically regulating neutrophil migration, GM-CSF controls lung dendritic cell function, which in turn promotes T-cell-dependent recruitment of neutrophils to the airways. We demonstrate that GM-CSF regulates lung dendritic cell antigen uptake, transport, and TH2/TH17 cell priming in an intrinsic fashion, which in turn drives pulmonary granulocyte recruitment and contributes to development of airway hyperresponsiveness in chronic disease. CONCLUSIONS: We identify GM-CSF as a potentially novel therapeutic target in chronic lung inflammation, describing a GM-CSF-dependent lung conventional dendritic cell-T-cell-neutrophil axis that drives chronic lung disease.
BACKGROUND:Steroid-resistant asthma is often characterized by high levels of neutrophils and mixed TH2/TH17 immune profiles. Indeed, neutrophils are key drivers of chronic lung inflammation in multiple respiratory diseases. Their numbers correlate strongly with disease severity, and their presence is often associated with exacerbation of chronic lung inflammation. OBJECTIVE: What factors drive development of neutrophil-mediated chronic lung disease remains largely unknown, and we sought to study the role of GM-CSF as a potential regulator in chronic asthma. METHODS: Different experimental animal models of chronic asthma were used in combination with alveolar macrophage-reconstitution of global GM-CSF receptor knockout mice as well as cell-type-specific knockout animals to elucidate the role of GM-CSF signaling in chronic airway inflammation. RESULTS: We identify GM-CSF signaling as a critical factor regulating pulmonary accumulation of neutrophils. We show that although being not required for intrinsically regulating neutrophil migration, GM-CSF controls lung dendritic cell function, which in turn promotes T-cell-dependent recruitment of neutrophils to the airways. We demonstrate that GM-CSF regulates lung dendritic cell antigen uptake, transport, and TH2/TH17 cell priming in an intrinsic fashion, which in turn drives pulmonary granulocyte recruitment and contributes to development of airway hyperresponsiveness in chronic disease. CONCLUSIONS: We identify GM-CSF as a potentially novel therapeutic target in chronic lung inflammation, describing a GM-CSF-dependent lung conventional dendritic cell-T-cell-neutrophil axis that drives chronic lung disease.
Authors: Julia Gschwend; Samantha P M Sherman; Frederike Ridder; Xiaogang Feng; Hong-Erh Liang; Richard M Locksley; Burkhard Becher; Christoph Schneider Journal: J Exp Med Date: 2021-08-25 Impact factor: 14.307