PMN‐MDSCs Orchestrate the Immunosuppressive Microenvironment in the Lung and Are Associated With Clinical Outcome in Bronchiectasis

ABSTRACT Background and Objective Myeloid‐derived suppressor cells (MDSCs) participate in the progression of many diseases including chronic lung diseases. However, whether MDSCs are accumulated in the lung and how MDSCs orchestrate the pulmonary microenvironment in bronchiectasis remains unknown. Here, we aim to test a hypothesis that PMN‐MDSCs are accumulated in the lung and play a role in creating an airway immunosuppressive milieu, thereby relating to clinical outcomes in bronchiectasis. Methods Flow cytometry and immunofluorescence staining were performed for analysing the frequencies and presence of PMN‐MDSCs, LOX‐1 + neutrophils, and ARG‐1 + PMN‐MDSCs in PBMCs, sputum, and lung tissues. T‐cell proliferation assays were established for evaluating the immunosuppressive activities of PMN‐MDSCs. RNA sequencing was performed to investigate the underlying mechanism of PMN‐MDSCs‐mediated immunosuppression. The relationship of PMN‐MDSCs with the time to next exacerbation and treatment response to antibiotic therapy was analysed. Results PMN‐MDSCs are accumulated in the lung and blood in bronchiectasis patients compared to healthy individuals. The majority of neutrophils in the lung of bronchiectasis patients are LOX‐1 + PMN‐MDSCs. Mechanistically, PMN‐MDSCs suppress T cell proliferation via secreting high levels of the enzyme arginase‐1 (ARG‐1). Notably, the frequencies of PMN‐MDSCs in sputum negatively correlate with the time to next exacerbation in bronchiectasis patients. Additionally, antibiotic therapy dramatically decreases PMN‐MDSCs frequencies in the airway of bronchiectasis patients. Conclusion These findings suggest that PMN‐MDSCs accumulate and establish an immunosuppressive microenvironment in the lung via ARG‐1 in bronchiectasis, which is associated with clinical outcome and response to antibiotic treatment, highlighting a potential role of PMN‐MDSCs in bronchiectasis progression. image