Lael M Yonker1, Anika Marand2, Sinan Muldur3, Alex Hopke3, Hui Min Leung4, Denis De La Flor5, Grace Park6, Hanna Pinsky6, Lauren B Guthrie6, Guillermo J Tearney7, Daniel Irimia3, Bryan P Hurley8. 1. Massachusetts General Hospital, Department of Pediatrics, Pulmonary Division, Boston, MA, United States; Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, MA, United States; Harvard Medical School, Department of Pediatrics, Boston, MA, United States. Electronic address: lyonker@mgh.harvard.edu. 2. Massachusetts General Hospital, Center for Engineering in Medicine, Boston, MA, United States; Shriners Hospital for Children, Boston, MA, United States. 3. Massachusetts General Hospital, Center for Engineering in Medicine, Boston, MA, United States; Harvard Medical School, Department of Surgery, Boston, MA, United States; Shriners Hospital for Children, Boston, MA, United States. 4. Massachusetts General Hospital, Wellman Center for Photomedicine, Boston, MA, United States; Harvard Medical School, Department of Dermatology, Boston, MA, United States. 5. Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, MA, United States. 6. Massachusetts General Hospital, Department of Pediatrics, Pulmonary Division, Boston, MA, United States. 7. Massachusetts General Hospital, Wellman Center for Photomedicine, Boston, MA, United States; Harvard Medical School, Department of Pathology, Boston, MA, United States; Harvard Medical School, Department of Dermatology, Boston, MA, United States. 8. Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, MA, United States; Harvard Medical School, Department of Pediatrics, Boston, MA, United States.
Abstract
BACKGROUND: Excessive neutrophil inflammation is the hallmark of cystic fibrosis (CF) airway disease. Novel technologies for characterizing neutrophil dysfunction may provide insight into the nature of these abnormalities, revealing a greater mechanistic understanding and new avenues for CF therapies that target these mechanisms. METHODS: Blood was collected from individuals with CF in the outpatient clinic, CF individuals hospitalized for a pulmonary exacerbation, and non-CF controls. Using microfluidic assays and advanced imaging technologies, we characterized 1) spontaneous neutrophil migration using microfluidic motility mazes, 2) neutrophil migration to and phagocytosis of Staphylococcal aureus particles in a microfluidic arena, 3) neutrophil swarming on Candida albicans clusters, and 4) Pseudomonas aeruginosa-induced neutrophil transepithelial migration using micro-optical coherence technology (µOCT). RESULTS: Participants included 44 individuals: 16 Outpatient CF, 13 Hospitalized CF, and 15 Non-CF individuals. While no differences were seen with spontaneous migration, CF neutrophils migrated towards S. aureus particles more quickly than non-CF neutrophils (p < 0.05). CF neutrophils, especially Hospitalized CF neutrophils, generated significantly larger aggregates around S. aureus particles over time. Hospitalized CF neutrophils were more likely to have dysfunctional swarming (p < 0.01) and less efficient clearing of C. albicans (p < 0.0001). When comparing trans-epithelial migration towards Pseudomonas aeruginosa epithelial infection, Outpatient CF neutrophils displayed an increase in the magnitude of transmigration and adherence to the epithelium (p < 0.05). CONCLUSIONS: Advanced technologies for characterizing CF neutrophil function reveal significantly altered migratory responses, cell-to-cell clustering, and microbe containment. Future investigations will probe mechanistic basis for abnormal responses in CF to identify potential avenues for novel anti-inflammatory therapeutics.
BACKGROUND: Excessive neutrophil inflammation is the hallmark of cystic fibrosis (CF) airway disease. Novel technologies for characterizing neutrophil dysfunction may provide insight into the nature of these abnormalities, revealing a greater mechanistic understanding and new avenues for CF therapies that target these mechanisms. METHODS: Blood was collected from individuals with CF in the outpatient clinic, CF individuals hospitalized for a pulmonary exacerbation, and non-CF controls. Using microfluidic assays and advanced imaging technologies, we characterized 1) spontaneous neutrophil migration using microfluidic motility mazes, 2) neutrophil migration to and phagocytosis of Staphylococcal aureus particles in a microfluidic arena, 3) neutrophil swarming on Candida albicans clusters, and 4) Pseudomonas aeruginosa-induced neutrophil transepithelial migration using micro-optical coherence technology (µOCT). RESULTS: Participants included 44 individuals: 16 Outpatient CF, 13 Hospitalized CF, and 15 Non-CF individuals. While no differences were seen with spontaneous migration, CF neutrophils migrated towards S. aureus particles more quickly than non-CF neutrophils (p < 0.05). CF neutrophils, especially Hospitalized CF neutrophils, generated significantly larger aggregates around S. aureus particles over time. Hospitalized CF neutrophils were more likely to have dysfunctional swarming (p < 0.01) and less efficient clearing of C. albicans (p < 0.0001). When comparing trans-epithelial migration towards Pseudomonas aeruginosa epithelial infection, Outpatient CF neutrophils displayed an increase in the magnitude of transmigration and adherence to the epithelium (p < 0.05). CONCLUSIONS: Advanced technologies for characterizing CF neutrophil function reveal significantly altered migratory responses, cell-to-cell clustering, and microbe containment. Future investigations will probe mechanistic basis for abnormal responses in CF to identify potential avenues for novel anti-inflammatory therapeutics.
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