**3. Neutrophils and the effect of** *CFTR* **mutations**

While bacteria and their products, cytokines and chemokines, are important triggers of neutrophil activation in CF airways, it is an emerging picture that a primary CFTR defect in cells of the innate immune system, including neutrophils, monocytes, and lymphocytes, contributes significantly to CF lung pathology [24]. Pharmacologic inhibition of CFTR and genetic mutation (F508del) in murine neutrophils activated the nuclear factor kappa‐light‐chain enhancer of activated B cells (NF‐κB) and increased macrophage inflammatory protein‐2 (MIP‐2) and TNF‐α production, as compared to non‐inhibited and control neutrophils. Interestingly, under LPS challenge, neutrophil‐depleted wild‐type mice reconstituted with F508del neutrophils displayed a more severe lung inflammation in comparison with neutrophil‐depleted wild‐type mice reconstituted with wild‐type neutrophils [98]. Altogether, these data strongly indicate that the lack of functional CFTR could result in excessive NF‐κB activation in neutrophils and therefore propagate a hyper‐inflammatory response.

CF neutrophils have a reduced phagocytic activity [19, 99] and defects in the respiratory burst, attributed to disrupted chloride transport to the phagolysosome [65, 100–102]. While wild‐type CFTR is transported to neutrophil phagosomes, the F508del protein is not targeted efficiently to these organelles [64], explaining why a correct chlorination of phagosomes in CF does not occur and hence the bactericidal defect. A still debated question is, however, the CFTR expression in neutrophils. Morris and colleagues, although found a defect in iC3b‐ mediated phagocytosis, did not detect CFTR in circulating and airway neutrophils by either immuno‐labelling or a Western blot [99]. Others found that CFTR expression was limited or undetectable in neutrophils by flow cytometry and also that no role for CFTR in neutrophil‐ mediated phagocytosis was observed [103]. On the other hand, Zhou and colleagues found CFTR at the phagosome level, although a lentiviral‐expressing system was used to achieve high protein levels. It might be that CFTR, expressed in hematopoietic stem/progenitor cells [104, 105], is down‐regulated to low levels during neutrophil maturation, which is nevertheless sufficient for neutrophil phagocytic and killing activities. The lack/dysfunction of CFTR in the bone marrow may lead to an irreversible functional defect. In this context, it is worth mentioning that knocking out CFTR in the myeloid compartment of mice resulted in poor survival, increased inflammation with recruitment of neutrophils, elevated cytokine production, and inability to resolve infection upon challenge with *P. aeruginosa*‐loaded agarose beads to mimic a chronic pulmonary infection [106].
