Pharmacological CFTR correction promotes an
anti-inflammatory phenotype of macrophages in the HF lung
Considering the high CFTR
positivity of peripheral and pulmonary monocytes and macrophages
(Supplemental Fig. 5A, 5B ), we explored the effects of
pharmacological CFTR correction on macrophages in the lung. Both
systemic and lung-specific Lum administration significantly increased
the overall number of pulmonary macrophages (Supplemental Fig.
6A ) with larger effects after o.t. application. The
treatment-associated increase of overall pulmonary macrophage counts was
mainly mediated by increases of non-alveolar macrophages
(Supplemental Fig. 6B ), which were more pronounced after o.t.
application. In contrast to systemic administration, o.t. administered
Lum markedly augmented the number of alveolar macrophages
(Supplemental Fig. 6C ). To understand whether this increase in
macrophages was beneficial or rather detrimental, we explored macrophage
activation profiles by determining the proportion of classically-
(CD80+) and alternatively- (CD206+)
activated cells within the pulmonary macrophage population. The
HF-associated augmentation of classically-activated macrophages was
alleviated by therapeutic Lum administration irrespective of application
route (Fig. 6a, d ). Likewise, therapeutic CFTR correction
significantly attenuated the HF-associated increase of non-alveolar
CD80+ macrophages (Fig. 6b, e ).
Interestingly, o.t. treated HF lungs presented with markedly higher
proportions of CD80+ alveolar macrophages
(Fig. 6c, f ), suggesting an application-induced
pro-inflammatory response. In contrast to CD80+macrophages, Lum induced higher proportions of alternatively-activated
macrophages overall as well as alveolar and non-alveolar irrespective of
treatment route (Fig. 6, Supplemental Fig. 7 andSupplemental Table 4 ). This is corroborated by increased
pulmonary IL-10 mRNA expression after systemic Lum administration
(Supplemental Fig. 8 ). In vitro , murine
macrophages (RAW246.7 cells) presented with reduced CFTR positivity
after PMA-induced activation, which was attenuated by CFTR correction
with Lum (Supplemental Fig. 9 ), suggesting an interplay between
CFTR surface expression and macrophage activation.