Broad Transcriptional Firing Represses Bactericidal Activity in Human Airway Neutrophils

Margaroli, Camilla; Giraldo, Diego Moncada; Gulick, Dalia; Dobosh, Brian; Giacalone, Vincent D.; Forrest, Osric; Sun, Fangxu; Gu, Chunhui; Wu, Ronghu; Gibson, Greg; Tirouvanziam, Rabindra

doi:10.2139/ssrn.3543838

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“…Future studies are needed to fully investigate a functional link between the depressed bacterial killing of monocytes recruited to CFASN and dysregulation of ISG15, CXCL11, NO, and interferon signaling in general, whose relationship to monocyte antibacterial activity is complex [ 15 , 28 , 39 , 40 , 41 ]. Interestingly, in a parallel effort to study transcriptional adaptations induced upon migration into CFASN in neutrophils, we found that broad changes caused by exposure to this milieu also caused a loss of killing ability toward P. aeruginosa in these cells [ 42 ]. Hence, the CF airway microenvironment negatively impacts incoming monocytes and neutrophils in their ability to kill bacteria, which may explain the paradoxical association of chronic airway inflammation with bacterial colonization in patients with CF.…”

Section: Discussionmentioning

confidence: 99%

Functional and Transcriptional Adaptations of Blood Monocytes Recruited to the Cystic Fibrosis Airway Microenvironment In Vitro

Ford

Giraldo

Margaroli

et al. 2021

IJMS

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Cystic fibrosis (CF) lung disease is dominated by the recruitment of myeloid cells (neutrophils and monocytes) from the blood which fail to clear the lung of colonizing microbes. In prior in vitro studies, we showed that blood neutrophils migrated through the well-differentiated lung epithelium into the CF airway fluid supernatant (ASN) mimic the dysfunction of CF airway neutrophils in vivo, including decreased bactericidal activity despite an increased metabolism. Here, we hypothesized that, in a similar manner to neutrophils, blood monocytes undergo significant adaptations upon recruitment to CFASN. To test this hypothesis, primary human blood monocytes were transmigrated in our in vitro model into the ASN from healthy control (HC) or CF subjects to mimic in vivo recruitment to normal or CF airways, respectively. Surface phenotype, metabolic and bacterial killing activities, and transcriptomic profile by RNA sequencing were quantified post-transmigration. Unlike neutrophils, monocytes were not metabolically activated, nor did they show broad differences in activation and scavenger receptor expression upon recruitment to the CFASN compared to HCASN. However, monocytes recruited to CFASN showed decreased bactericidal activity. RNASeq analysis showed strong effects of transmigration on monocyte RNA profile, with differences between CFASN and HCASN conditions, notably in immune signaling, including lower expression in the former of the antimicrobial factor ISG15, defensin-like chemokine CXCL11, and nitric oxide-producing enzyme NOS3. While monocytes undergo qualitatively different adaptations from those seen in neutrophils upon recruitment to the CF airway microenvironment, their bactericidal activity is also dysregulated, which could explain why they also fail to protect CF airways from infection.

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