Abstract
Cystic Fibrosis (CF) is an inherited pleiotropic disease that results from abnormalities in the gene that codes for the chloride channel, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CF patients are frequently colonized by several pathogens, but the mechanisms that allow colonization in spite of apparently functional immune systems are incompletely understood. In this paper we show that blood peripheral monocytes isolated from CF patients are found in an endotoxin tolerance state, yet this is not due to a deficient TLR activation. On the other hand, levels of the amplifier of inflammatory responses, TREM-1 (Triggering Receptor Expressed on Myeloid cells), are notably down-regulated in monocytes from patients, in comparison to those extracted from healthy volunteers. Furthermore, the soluble form of TREM-1 (sTREM-1) was not detected in the sera of patients. Additionally, and in strict contrast to patients who suffer from Chronic Obstructive Pulmonary Disease (COPD), CF monocytes challenged ex vivo with LPS neither up-regulated membrane-anchored TREM-1 nor sTREM-1. Finally, similar levels of PGE2 expression and p65 translocation into the nucleus were found in both patients and healthy volunteers, thus suggesting that TREM-1 regulation is neither controlled by PGE2 levels nor by p65 activation in this case. However, PU.1 translocation into the nucleus was significantly higher in CF monocytes than in controls, suggesting a role for this transcription factor in the control of TREM-1 expression. We conclude that down-regulation of TREM-1 expression in cystic fibrosis patients is at least partly responsible for the endotoxin tolerance state in which their monocytes are locked.
Highlights
Cystic fibrosis (CF), called mucoviscidosis, is a complex, pleiotropic disease that affects all exocrine epithelia
We demonstrate that TREM-1 levels are clearly down-regulated in monocytes from patients when compared to healthy volunteers and to patients suffering from another pulmonary disease, Chronic Obstructive Pulmonary Disease (COPD)
We have previously described that the pseudokinase, IRAK-M, is overexpressed in monocytes from patients who suffer from Acute Coronary Syndrome, and is involved in the endotoxin tolerance phenomenon observed in these monocytes [33]
Summary
Cystic fibrosis (CF), called mucoviscidosis, is a complex, pleiotropic disease that affects all exocrine epithelia. CF results from abnormalities in the gene that codes for the chloride channel termed CF Transmembrane Conductance Regulator (CFTR), which belongs to the extended family of ATP-binding cassette (ABC) transporter ATPases [1,2]. This transmembrane glycoprotein is expressed in some epithelia, and controls chloride flux across cell surfaces. Other authors claim that a deficit of hydrophilic surfactant proteins contributes to the inefficiency of the cellular inflammatory response to invading bacteria [5] These observations, in turn, point to a deregulation of the innate immune systems in CF patients, and provoke a thorough analysis of the interplay between bacterial and host factors
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