Carcinoembryonic antigen (CEA)-related cell adhesion molecules are co-expressed in the human lung and their expression can be modulated in bronchial epithelial cells by non-typable Haemophilus influenzae, Moraxella catarrhalis, TLR3, and type I and II interferons

Klaile, Esther; Klassert, Tilman E; Scheffrahn, Inka; Müller, Mario M; Heinrich, Annina; Heyl, Kerstin A; Dienemann, Hendrik; Grünewald, Christiane; Bals, Robert; Singer, Bernhard B; Slevogt, Hortense

Here we present the first comprehensive study based on immunohistochemistry demonstrating that CEACAM1, CEACAM5, and CEACAM6 are frequently co-expressed in several tissues of the human lung, including epithelia of the airways and alveoli. CEACAM expression was not connected to COPD, smoking status and granulocyte infiltration ( Figure 1 , Tables 3 and 4 ). Despite the analysis of non-cancer tissues from the specimen, the fact that the lung sections used for immunohistochemical analysis were from patients that underwent lung resection to treat lung cancer might conceal a regulatory effect of COPD or smoking status on CEACAM expression, since CEACAM1, CEACAM5, and CEACAM6 have all been shown to be up-regulated in lung cancer [49] [50] [51] [52] [53] . Also, the inflammatory processes associated with cancers of the lung might have had an effect on the expression levels of the CEACAMs. For example, as discussed below, IFNγ can up-regulate CEACAMs 1, 5, and 6. Importantly, we show that the COPD-associated pathogens M. catarrhalis and NTHi can also upregulate CEACAM1 expression independent of their ability to bind to CEACAM1. The up-regulation by M. catarrhalis might be at least in part due to the induction of IFNβ production ( Figure 5G ) and is in accordance with the observation of CEACAM1 up-regulation by pathogenic Neisseria in endothelial and epithelial cells [54, 55] . CEACAM5 and CEACAM6 expression levels were not affected by M. catarrhalis and NTHi. However, both receptors were already expressed at high levels and in all specimens (Figure 1, Tables 2 and 3 ). Regarding colonization, the increase in CEACAM1 on epithelial cells upon bacterial challenge is likely to increase bacterial adherence and infection. This interaction would be facilitated by an impaired mucocilliary clearance, which is associated with later phases of COPD. Thus, CEACAM receptors might be at least in part responsible for the colonization of the lower airways by M. catarrhalis and NTHi in COPD patients. This setting would also explain the association of bacterial colonization with progressive/ advanced disease despite the fact that we did not find a regulation of CEACAM expression by the chronic pathologic conditions COPD, smoking status and granulocyte infiltration (Figure 1, Tables 3 and 4) . Further studies including identification of pathogens in the lower airways will be necessary to shed light on this aspect of CEACAM-pathogen interactions. It will be also important to take into account that an up-regulation of CEACAMs might be transient either due to temporary qualities of chronic/persistent disease or due to pathogen characteristics at distinct time points during the infection process. It will also be interesting to test human lung tissues for the presence of the other CEACAMs expressed on epithelial cells (CEACAM7, 18, 20 and 21 [56, 57] ) and to analyze their ability to interact with pathogens.