Project Summary
Patients with cystic fibrosis (CF) suffer from chronic infections and lung inflammation leading to bronchiectasis
and, ultimately, respiratory failure. Although recent advances, including the approval of highly effective CFTR
modulator therapy (HEMT), have improved the overall quality of life of people with CF (PwCF), chronic
infection and inflammation are the primary cause of morbidity. Although the magnitude of the inflammatory
response is known to be increased in the CF lung, the mechanisms underlying persistent inflammation are
unknown. We have shown that lung macrophages are critical to the local inflammatory response in CF. Lung
macrophages include resident lung macrophages, as well as lung macrophages that are recruited to the lung
in response to inflammatory stimuli. Our preliminary data demonstrate that CF recruited lung macrophages
have decreased expression of Nrf2, a transcription factor known to regulate cellular metabolism, compared to
non-CF bronchiectasis and control subjects, and this did not improve with HEMT. We also found that CF
recruited lung macrophages are persistently glycolytic and inflammatory, even in the setting of HEMT, while
non-CF bronchiectasis and healthy recruited lung macrophages can transition to an inflammation resolving
phenotype. As immune cell crosstalk can be mediated by extracellular vesicles (EVs), we investigated the
impact of resident lung macrophage EVs on the inflammatory response of recruited lung macrophages and
found that CF resident lung macrophage EVs induce persistent inflammation in recruited lung macrophages.
Lastly, we have preliminary data showing increased miRNAs predicted to inhibit Nrf2 and reduced levels of
inflammation resolving lipids in EVs from CF resident lung macrophages. Thus, we hypothesize that specific
miRNAs and lipids within CF resident LM EVs reduce Nrf2 levels in recruited LMs, causing persistent
glycolysis and failure to transition to an inflammation resolving phenotype. In Aim 1, we will test the hypothesis
that there are functionally important immunometabolic differences in CF lung macrophages that are specific to
CF and persist after HEMT. In this Aim, we will fully characterize subpopulations of lung macrophages in the
CF lung and will quantify differences in cellular metabolism and inflammation resolution between resident and
recruited lung macrophages in PwCF, non-CF bronchiectasis subjects, and healthy subjects. In Aim 2, we will
test the hypothesis that specific miRNAs within EVs released by CF resident lung macrophages impact the
inflammatory response of recruited lung macrophages. In Aim 3, we will test the hypothesis that the lipid
content of EVs released by CF resident lung macrophages prevents the shift to an inflammation resolution
phenotype in recruited lung macrophages. The proposed studies are unique because they involve human
subjects before and after HEMT and thus, our data will be directly relevant to PwCF. In addition, our studies
will provide new and essential information on the mechanisms of persistent lung inflammation in CF and will
allow us to identify targets for novel therapies to reduce harmful CF lung inflammation and improve the lives
and longevity of people living with CF.