Soluble CEACAM8 interacts with CEACAM1 inhibiting TLR2-triggered immune responses.

Bernhard B Singer,Ramona Binding-Liermann,Luis Carlos Berrocal-Almanza,Frauke Schreiber,Kerstin A Heyl,Hortense Slevogt,Janine Zweigner,Mario M Müller,Annina Heinrich,Lena Opp,Andreas Weimann,Dat Quoc Tran

doi:10.1371/journal.pone.0094106

Abstract

Lower respiratory tract bacterial infections are characterized by neutrophilic inflammation in the airways. The carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 8 is expressed in and released by human granulocytes. Our study demonstrates that human granulocytes release CEACAM8 in response to bacterial DNA in a TLR9-dependent manner. Individuals with a high percentage of bronchial lavage fluid (BALF) granulocytes were more likely to have detectable levels of released CEACAM8 in the BALF than those with a normal granulocyte count. Soluble, recombinant CEACAM8-Fc binds to CEACAM1 expressed on human airway epithelium. Application of CEACAM8-Fc to CEACAM1-positive human pulmonary epithelial cells resulted in reduced TLR2-dependent inflammatory responses. These inhibitory effects were accompanied by tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 and by recruitment of the phosphatase SHP-1, which could negatively regulate Toll-like receptor 2-dependent activation of the phosphatidylinositol 3-OH kinase-Akt kinase pathway. Our results suggest a new mechanism by which granulocytes reduce pro-inflammatory immune responses in human airways via secretion of CEACAM8 in neutrophil-driven bacterial infections.

Highlights

The recruitment of neutrophils is one of the most important components of the initial, innate immune response of the human lung to bacterial infections [1]
In our study we demonstrated that approximately 0.5–1 ng CEACAM8 was secreted by 16106 granulocytes
In the study presented here, for the first time we provide evidence that soluble CEACAM8 dampened the TLR2-triggered immune response of CEACAM1-expressing human pulmonary epithelial cells

Summary

Introduction

The recruitment of neutrophils is one of the most important components of the initial, innate immune response of the human lung to bacterial infections [1]. Toll-like receptor (TLR) 2, expressed on the apical surface of airway epithelial cells, is important for the detection of inhaled bacteria in the human airways and the initiation of the innate immune response [2]. Neutrophils express all TLRs except TLR3 [3] Despite their active role in the pro-inflammatory immune response, neutrophils are part of the cellular network that orchestrates the resolution of inflammation by secreting a variety of molecules that possess anti-inflammatory effects in order to avoid tissue damage [3]. The crosstalk seen in the course of bacterial infection between neutrophil granulocytes and the airway epithelium for relieving inflammation, as well as decreasing their recruitment, are not well understood

Methods

Results

Conclusion