Location / Meeting Link: HSRBII, N600 [https://emory.zoom.us/j/98452979800] 

                                                                                                     
Committee Members:
Rabin Tirouvanziam, PhD (Co-Advisor); Krish Roy, PhD (Co-Advisor); Karmella Haynes, PhD; Jamal Lewis, PhD; Shuichi Takayama, PhD


Title: Biomimetic model of human small airway monocyte and macrophage recruitment, adaptation, and function

Abstract:
Several muco-obstructive lung diseases in humans, including cystic fibrosis (CF), feature chronic recruitment of blood leukocytes and their reprogramming within the small-airway lumen, driving pathological adaptations such as dysregulated immune-mediator secretion and impaired bacterial killing.  Most current studies focus on neutrophils or rely on in vivo/in vitro models that do not capture the nuances of the small airway.  To investigate these mechanisms, we engineered a biomimetic small-airway model in which primary human blood monocytes transmigrate across a human small-airway epithelium and, after 4-day exposure to macrophage colony-stimulating factor (M-CSF), differentiate into macrophages.  Airway-recruited monocytes (ArMos), generated using the control chemoattractant CCL2, underwent phenotypic, transcriptomic, and secretomic reprogramming upon transmigration and further changes upon differentiation into airway-recruited macrophages (ArMas), relative to circulating monocytes.  Compared with non-transmigrated, M-CSF–differentiated macrophages, both ArMos and ArMas retained airway-associated features that are otherwise lost ex vivo.  Conditioning with CF airway supernatant (cell- and bacteria-free sputum) produced additional, specific alterations in ArMos and ArMas across phenotype, transcriptome, and secretome compared with CCL2 conditions.  Critically, CF ArMas (but not CF ArMos) showed a markedly reduced ability to kill Pseudomonas aeruginosa, a common CF pathogen.  These findings extend prior work on small-airway–recruited neutrophils and identify macrophage immune tolerance as one contributor to bacterial colonization in CF.  Our biomimetic model supports further mechanistic and preclinical investigations of small airway-recruited monocytes and macrophages in health and CF, as well as in other diseases featuring chronic airway inflammation and infection, such as non-CF bronchiectasis and chronic obstructive pulmonary disease (COPD).