We read with great interest the comment by Krysko and coworkers on our recently published article (1). In addition, we have also reviewed other results reported by this group regarding the etiology of cystic fibrosis (CF).
Previous data from our laboratory had indicated that circulating monocytes from CF patients are “locked” in an endotoxin refractory state (2), and these results were confirmed in the referred study (1). Briefly, we screened circulating cells from 25 CF patients for cytokine production, phagocytosis ability, and Ag presentation. We observed a drastic down-regulation of both proinflammatory cytokines (TNF-α, IL-6, IL-12, and IL-23) and a subset of chemokines (CCL3, CCL4, CCL20, and CCL22) in ex vivo LPS-stimulated monocytes from these patients in comparison to those from healthy volunteers. Furthermore, CF monocytes exhibited high CD64 and low MHC II expression levels, which correlated with high phagocytic activity and low Ag presentation ability. We concluded that the phenotype of circulating CF monocytes mirrors the endotoxin tolerance state (sometimes termed M2) in a pathological setting. (macrophages/monocytes can be classified as M1 or M2 depending on their response to stimulation with specific pathogen-associated molecular patterns such as LPS; Ref. 3). Our findings might explain why, despite a high frequency of infection in CF patients, they do not suffer from a permanent hyperinflammatory state and the inflammatory response is localized. We stress that our work focused on circulating monocytes, and no resident cells from these patients were analyzed.
Data from Dr. Bachert’s group, on the contrary, indicate that resident macrophages in nasal polyps from CF patients exhibit some proinflammatory markers (4, 5); these authors deduce a predominant M1 phenotype for these cells. However, it is important to note that these markers were analyzed in total extracts, not in purified macrophages exposed to LPS ex vivo. In addition, there are differences between both studies that might limit the comparison of results. Few articles have directly compared inflammatory parameters in upper and lower airways (6). In particular, nasal polyps may not faithfully reflect the inflammatory response in the lower airways. Although the reported prevalence of nasal polyposis in CF patients varies from 7 to 48% (7), it must be considered that nasal polyps do not constitute a primary manifestation of CF but a frequent complication. Polyps are a consequence of conditions that cause chronic inflammation in the nose and nasal sinuses characterized by stromal edema and variable cellular infiltrate (8) and might represent a proliferative airway repair mechanism (7).
Furthermore, Krysko and coworkers base their conclusions on data from children (mean age: 13 years) who suffer from CF and have visible nasal polyps. It is currently not possible to compare critical parameters (e.g., mutations in the CFTR gene, bacterial colonization status, or clinical manifestations) of both cohorts of patients. However, it is important to consider that children with CF who have visible nasal polyps have less severe lung disease than age-matched peers (7). Additionally, the most common bacteria isolated from the sinuses of CF patients vary with age. Whereas Pseudomonas aeruginosa appears to be more significant in elders, Staphylococcus aureus and Haemophilus influenzae are found predominately in younger patients (9).
Finally, and despite the limitations of the nasal polyps as a model for the study of the lower airways in CF patients, our findings are compatible with previous reports by other authors. In fact, it has been reported that primary respiratory epithelial cells cultured from nasal polyps of these patients are not responsive to P. aeruginosa or IL-1β/H2O2 challenge (10), suggesting a deregulated inflammatory response.
