Abstract
BackgroundEarly in life, cystic fibrosis (CF) patients are infected with microorganisms. The role of macrophages has largely been underestimated in literature, whereas the focus being mostly on neutrophils and epithelial cells. Macrophages may however play a significant role in the initiating stages of this disease, via an inability to act as a suppressor cell. Yet macrophage dysfunction may be the first step in cascade of events leading to chronic inflammation/infection in CF. Moreover, reports have suggested that CFTR contribute to altered inflammatory response in CF by modification of normal macrophage functions.ObjectivesIn order to highlight possible intrinsic macrophage defects due to impaired CFTR, we have studied inflammatory cytokines secretions, recognition of pathogens and phagocytosis in peripheral blood monocyte-derived macrophages from stable adult CF patients and healthy subjects (non-CF).ResultsIn CF macrophage supernatants, concentrations of sCD14, IL-1β, IL-6, TNF-α and IL-10 were strongly raised. Furthermore expression of CD11b and TLR-5 were sorely decreased on CF macrophages. Beside, no difference was observed for mCD14, CD16, CD64, TLR-4 and TLR1/TLR-2 expressions. Moreover, a strong inhibition of phagocytosis was observed for CF macrophages. Elsewhere CFTR inhibition in non-CF macrophages also led to alterations of phagocytosis function as well as CD11b expression.ConclusionsAltogether, these findings demonstrate excessive inflammation in CF macrophages, characterized by overproduction of sCD14 and inflammatory cytokines, with decreased expression of CD11b and TLR-5, and impaired phagocytosis. This leads to altered clearance of pathogens and non-resolution of infection by CF macrophages, thereby inducing an exaggerated pro-inflammatory response.
Highlights
Lung problem is the dominant clinical feature consequence of chronic excessive inflammation, and accounts for morbidity and mortality in patients with Cystic Fibrosis (CF), an autosomal recessive disorder caused by mutations in gene encoding Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein [1,2]
To determine whether macrophages participate to chronic inflammation in cystic fibrosis (CF) pathophysiology, we have investigated production of major pro-inflammatory cytokines/chemokines by macrophages
TNF-α, IL-6 and IL-10 levels were significantly increase in CF macrophage supernatants (Figure 1C/E/F) whereas low levels of IFN-γ were secreted by macrophages with no significant difference between non-CF and CF macrophages (Figure 1D)
Summary
Lung problem is the dominant clinical feature consequence of chronic excessive inflammation, and accounts for morbidity and mortality in patients with Cystic Fibrosis (CF), an autosomal recessive disorder caused by mutations in gene encoding Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein [1,2]. In response to lipopolysaccharide (LPS) from P. aeruginosa, bronchoalveolar lavage fluids (BALF) of CFTR-/- mice were characterized by significantly higher concentrations of proinflammatory cytokines released by macrophages, such as IL-1α, IL-6, G-CSF and IL-8, than BALF from wild type (WT) mice. Elsewhere CFTR inhibition in non-CF macrophages led to alterations of phagocytosis function as well as CD11b expression. Conclusions: Altogether, these findings demonstrate excessive inflammation in CF macrophages, characterized by overproduction of sCD14 and inflammatory cytokines, with decreased expression of CD11b and TLR-5, and impaired phagocytosis. This leads to altered clearance of pathogens and non-resolution of infection by CF macrophages, thereby inducing an exaggerated pro-inflammatory response
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