CFTR Modulator Therapy Enhances Peripheral Blood Monocyte Contributions to Immune Responses in People With Cystic Fibrosis

• DOI: 10.3389/fphar.2020.01219
• Publication Date: 2020-08-13T05:33:53Z
• Authors: Katherine B. Hisert; Timothy P. Birkland; Kelly Q. Schoenfelt; Matthew E. Long; Brenda Grogan; Suzanne Carter; W. Conrad Liles; Edward F. McKone; Lev Becker; Anne M. Manicone; Sina A. Gharib
• Keywords: Ivacaftor; Monocyte

CFTR modulators decrease some etiologies of CF airway inflammation; however, data indicate that non-resolving infection and inflammation persist in individuals with chronic bacterial infections. Thus, identification therapies diminish without allowing unrestrained growth remains a critical research goal. Novel strategies for combatting deleterious the modulator era require better understanding cellular contributions to disease, how inflammatory cells change after initiation therapy. Peripheral blood monocytes, which traffic airway, can develop both pro-inflammatory inflammation-resolving phenotypes, represent intriguing targets focused therapies. This therapeutic approach, requires more detailed knowledge monocyte programming phenotypes.In order characterize phenotype these therapy, we studied adults (n=10) CF, infections, CFTR-R117H mutations before 7 days ivacaftor. Transcriptomes freshly isolated monocytes were interrogated by RNA-sequencing (RNA-seq) followed pathway-based analyses. Plasma concentrations cytokines chemokines evaluated multiplex ELISA.RNAseq identified approximately 50 genes basal expression was significantly changed all 10 subjects Of these, majority increased post ivacaftor, including many traditionally associated enhanced immune responses. Pathway analyses confirmed transcriptional programs overwhelmingly up-regulated biological modules immunity, cell cycle, oxidative phosphorylation, unfolded protein response. Ivacaftor plasma CXCL2, neutrophil chemokine secreted macrophages, CCL2, chemokine.Our results demonstrate ivacaftor causes acute changes profiles chemokines, suggest signals myeloid trafficking may contribute people taking modulators. To our knowledge, this is first report investigating transcriptomic response circulating treated modulator.