Immunomodulation in Cystic Fibrosis: Why and How?

Abstract

Cystic fibrosis (CF) lung disease is characterized by unconventional mechanisms of inflammation, implicating a chronic immune response dominated by innate immune cells. Historically, therapeutic development has focused on the mutated cystic fibrosis transmembrane conductance regulator (CFTR), leading to the discovery of small molecules aiming at modulating and potentiating the presence and activity of CFTR at the plasma membrane. However, treatment burden sustained by CF patients, side effects of current medications, and recent advances in other therapeutic areas have highlighted the need to develop novel disease targeting of the inflammatory component driving CF lung damage. Furthermore, current issues with standard treatment emphasize the need for directed lung therapies that could minimize systemic side effects. Here, we summarize current treatment used to target immune cells in the lungs, and highlight potential benefits and caveats of novel therapeutic strategies.

Mechanistic analysis and significance of sphingomyelinase‐mediated decreases in transepithelial CFTR currents in nHBEs

“…This dihydroceramide was already increased in cfHBEs as compared to nHBEs, indicating that treatment pushed this dihydroceramide even further away from the nHBE levels. (e-h) In regard to sphingomyelin, both VX445 + VX661 and VX445 + VX661 + VX770 decreased four sphingomyelins of interest, with no difference between the two treatments pulmonary pathophysiology of CF and are present in much higher abundance in CF airways than other immune cells (Giacalone et al, 2020). Thus, we resolved to determine the presence of cellular and secreted acid-SMase in transmigrated neutrophils.…”

“…AMPK, cystic fibrosis transmembrane conductance regulator, epithelial cells, modulator therapy, neutrophils, sphingomyelinase secretion from bronchial epithelial cells, as well as from airway-like neutrophils, which are highly prevalent in the CF lung (Giacalone et al, 2020).…”

Regulatory mechanisms of neutrophil migration from the circulation to the airspace

“…A final complication for therapeutic development that is worth noting is that PMNs can undergo marked functional and phenotypic changes after recruitment to the airspace. This is particularly well documented in the CF airway, where PMNs exhibit enhanced degranulation and oxidant generation (potentially exacerbating lung injury) but impaired bacterial killing [ 277 ]. This PMN phenotype, recently coined ‘GRIM’ (granule releasing, immunomodulatory, metabolically active), can be mimicked in vitro by inducing PMN TEpM with CF airway secretions [ 278 ].…”

Physical Activity Regulates TNFα and IL-6 Expression to Counteract Inflammation in Cystic Fibrosis Patients

“…In CF, inflammation plays a critical role in lung pathology and disease progression; this makes the disease an interesting area of research with broad therapeutic relevance [ 4 , 5 , 6 ]. Indeed, in the airways of CF patients, the epithelial cells become deficient in transmembrane conductance regulator (CFTR) through abnormal processes; as such, the transcription of inflammatory molecules is activated [ 7 ].…”