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Azithromycin Reduces Exaggerated Cytokine Production by M1 Alveolar Macrophages in Cystic Fibrosis

¹ Department of Clinical Chemistry, ² Unit of Industrial Toxicology and Occupational Medicine, and ³ Division of Paediatric Pulmonology, Université Catholique de Louvain, Brussels, Belgium; and ⁴ Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands

Correspondence and requests for reprints should be addressed to Teresinha Leal, M.D., Ph.D., Clinical Chemistry, Université catholique de Louvain, Ave Hippocrate 10, Brussels, Belgium. E-mail: teresinha.leal{at}uclouvain.be

Macrophages phagocyte pathogenic microorganisms and orchestrate immune responses by producing a variety of inflammatory mediators. The cystic fibrosis (CF) transmembrane conductance regulator chloride channel has been reported to be of pivotal importance for macrophage functions. The exact phenotype and role of macrophages in CF is still unknown. Alveolar and peritoneal macrophages were monitored in CF mice homozygous for the F508 del mutation and in wild-type control animals. Classical (M1) and alternative (M2) macrophage polarization and responses to LPS from Pseudomonas aeruginosa were investigated, and the effect of azithromycin was examined in both cell populations. We show that alveolar macrophage counts were 1.7-fold higher in CF as compared with wild-type mice. The macrophage-related chemokine, chemokine C-C motif ligand (CCL)-2, was found to be at least 10-fold more abundant in the alveolar space of mutant mice. Cell count and CCL-2 protein levels were also increased in the peritoneal cavity of CF mice. Both M1 and M2 macrophage polarization were significantly enhanced in alveolar and peritoneal cells from F508del-CF mice as compared with control animals. LPS-stimulated expression of proinflammatory mediators, such as nitric oxide synthase-2, IL-1β, and CCL-2, was increased, whereas anti-inflammatory IL-10 expression was decreased in CF macrophages. Azithromycin, added to cell cultures at 1 mg/liter, significantly reduced proinflammatory cytokine expression (IL-1β, CCL-2, TNF-) in M1-induced CF and wild-type alveolar macrophages. Our findings indicate that CF macrophages are ubiquitously accumulated, and that these cells are polarized toward classical and alternative activation status. Azithromycin down-regulates inflammatory cytokine production by M1-polarized CF alveolar macrophages.

Key Words: cystic fibrosis • cystic fibrosis transmembrane conductance regulator • inflammation • macrophages • azithromycin

CLINICAL RELEVANCE The exact phenotype and role of macrophages in cystic fibrosis (CF) is unknown. Azithromycin exerts beneficial effects in CF, but its precise mechanism of action remains unclear. We show here that CF macrophages are ubiquitously accumulated, and that these cells are polarized toward classical M1 and alternative M2 activation status. Azithromycin down-regulates inflammatory cytokine production by M1-polarized CF alveolar macrophages.