Abstract
Apical localization of Intercellular Adhesion Receptor (ICAM)-1 regulates the adhesion and guidance of leukocytes across polarized epithelial barriers. Here, we investigate the molecular mechanisms that determine ICAM-1 localization into apical membrane domains of polarized hepatic epithelial cells, and their effect on lymphocyte-hepatic epithelial cell interaction. We had previously shown that segregation of ICAM-1 into apical membrane domains, which form bile canaliculi and bile ducts in hepatic epithelial cells, requires basolateral-to-apical transcytosis. Searching for protein machinery potentially involved in ICAM-1 polarization we found that the SNARE-associated protein plasmolipin (PLLP) is expressed in the subapical compartment of hepatic epithelial cells in vitro and in vivo. BioID analysis of ICAM-1 revealed proximal interaction between this adhesion receptor and PLLP. ICAM-1 colocalized and interacted with PLLP during the transcytosis of the receptor. PLLP gene editing and silencing increased the basolateral localization and reduced the apical confinement of ICAM-1 without affecting apicobasal polarity of hepatic epithelial cells, indicating that ICAM-1 transcytosis is specifically impaired in the absence of PLLP. Importantly, PLLP depletion was sufficient to increase T-cell adhesion to hepatic epithelial cells. Such an increase depended on the epithelial cell polarity and ICAM-1 expression, showing that the epithelial transcytotic machinery regulates the adhesion of lymphocytes to polarized epithelial cells. Our findings strongly suggest that the polarized intracellular transport of adhesion receptors constitutes a new regulatory layer of the epithelial inflammatory response.
Highlights
The type I transmembrane protein intercellular adhesion molecule (ICAM)-1 is the counterreceptor of leukocyte β2-integrins and mediates the firm adhesion of leukocytes to epithelial and endothelial cells [1,2,3]
HepG2 cells are spontaneously polarized human hepatic epithelial cells that form bile canalicular-like structures (BCs) with a spherical shaped-lumen sealed by tight junctions (TJs) and surrounded by the subapical compartment (SAC), which could be detected by expressing GFP-Rab11 (Fig. 1b)
Despite its preferential apical localization, ICAM-1 accumulates at the basolateral plasma membrane (Fig. 1c), which is accessible from the extracellular milieu
Summary
The type I transmembrane protein intercellular adhesion molecule (ICAM)-1 is the counterreceptor of leukocyte β2-integrins and mediates the firm adhesion of leukocytes to epithelial and endothelial cells [1,2,3]. ICAM-1 is apically confined in polarized intestinal and hepatic epithelia [2, 4, 5]. Such polarization confers on these cellular barriers the capacity to establish a haptotactic gradient between apical and basolateral membrane domains, which guides infiltrated immune cells [2, 6]. ICAM-1 is mostly confined in these apical structures and is not accessible to circulating immune cells, which preferentially adhere to hepatic epithelial cells when.
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