Monocytes from Cystic Fibrosis Patients Are Locked in an LPS Tolerance State: Down-Regulation of TREM-1 as Putative Underlying Mechanism

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.

NFκB2/p100 Is a Key Factor for Endotoxin Tolerance in Human Monocytes: A Demonstration Using Primary Human Monocytes from Patients with Sepsis

“…Although the underlying mechanisms implicated in ET have been extensively studied, including reprogrammed epigenetic, microRNAs, and several molecules (1,7,27,28), a complete picture of this process is still lacking. In-depth studies of ET have analyzed the participation of a number of factors and have established the role of several negative regulators, such as IRAK-M, ST2, suppressor of cytokine signaling 1, short version of MyD88 and SHIP, as well as the dysregulation of TLR4 and TREM-1 (4,12,29,30), roles that have been observed occasionally in different models (1,9).…”

“…Circulating cells isolated from patients with sepsis show a reduced capacity to produce proinflammatory cytokines when stimulated with an endotoxin ex vivo (3,4). ET has also been observed for other pathologies such as acute coronary syndrome (5) and cystic fibrosis (6)(7)(8).…”

“…Real-time quantitative PCRs were performed using the QuantiMix Easy SYG kit from Biotools and specific primers. Results were normalized to the expression of the b-actin (actin), and the cDNA copy number of each gene of interest was determined using a 7-point standard curve, as described previously (4,5,7,20,21).…”

Triggering receptor expressed on myeloid cells -1 as a new therapeutic target during inflammatory diseases

“…TREM-1 was shown to be expressed at low levels in lung resident macrophages and circulating monocytes from CF patients. This phenomena was associated with a failure to mount an appropriate inflammatory response, 67,68 along with an impairment of antigen presentation properties. Those monocytes expressed elevated levels of PU.1, a transcription factor that counteracts the TLRs-induced TREM-1 upregulation.…”

Involvement of the TREM-1/DAP12 pathway in the innate immune responses to Porphyromonas gingivalis

“…Monocytes are a major source of TREM-1 in inflammation (Arts et al, 2011;Cavaillon, 2009;Ferat-Osorio et al, 2009;Wong-Baeza et al, 2006) and their expression has been shown to be regulated in several bacterial and fungal infections, including infections of the respiratory track, gut or amniotic fluid (Aoki et al, 2004;Begum et al, 2004;Buckland et al, 2011;del Fresno et al, 2008;How et al, 2011;Kusanovic et al, 2011;Richeldi et al, 2004;Schmausser et al, 2008). Individual microbial components, such as lipopolysaccharide (LPS) and peptidoglycan, can cause up-regulation of cell surface-localized TREM-1 by monocytes, as well as release in its soluble (s)TREM-1 form (Begum et al, 2004;Gibot et al, 2004b;Gomez-Pina et al, 2007;Murakami et al, 2007;Ramanathan et al, 2005;Zeng et al, 2007).…”