The role of ABC transporters in the innate immune system

The innate immune system, located in the skin and the mucous membranes is a highly complex physical and chemical barrier providing a first line defense against intrusion of a large number of potentially harmful compounds. It protects the whole body and in particular sensitive organs. Two types of molecules, the membrane anchored pattern recognition receptors (PRRs) and the transmembrane ATP binding cassette (ABC) transporters, driven by ATP hydrolysis, contribute to the barrier integrity. Both systems recognize and bind a large number of chemically highly diverse compounds within the lipid bilayer membrane and prevent their intrusion into the cytosol. Interestingly, they both recognize the same types of hydrogen bond acceptor patterns, differ however with respect to charge specificity. In analogy to PRRs, ABC transporters could thus be called pattern recognition transporters (PRTs). As ABC transporters (or PRTs) require one molecule of ATP per transport event, high transporter activity leads to a high rate of ATP synthesis and concomitantly to the production of reactive oxygen species (ROS) in mitochondria. ROS activate the nuclear factor kappa B (NF-B), which is a driver of inflammation, inducing cytokines and interleukins. PRRs act via various other immune signaling cascades.



Although ABC transporters have been well studied in the context of multidrug resistance (MDR), their physiologically relevant functions and their significant roles in cellular immune signaling remains to be elucidated in more detail. Transporter activation starts at a compound-specific concentration, the rate of transport increases with increasing concentration, reaches a maximum and decreases again at higher concentrations, when more than one molecule is bound to the transporter. The different “working conditions” and “operation times” of ABC transporters lead to different metabolic and immunological states of the cell protected by these transporters. Strong long-term activation of transporters may lead to strong ROS signaling and ultimately to transporter downregulation followed by membrane exhaustion, which may have fatal consequences. Functional reconstitution of the protective power of ABC transporters is therefore worth to be studied. It may be possible e.g. by transporter induction via nuclear receptors (such as the pregnane X receptor, PXR) or as recently demonstrated via extracellular vesicle-mediated transfer of ABC transporters to the exhausted membranes (i.e. exofection).



We would like to stimulate work providing molecular, physiological, and immunological insights into the role of ABC transporters in cellular immunity in single cells, animals (including fish), and humans. The focus of interest is on connecting the extent and duration of ABC transporter activation with the immune cascades triggered. In this context, the following questions may be asked:

- When do molecules interacting with ABC transporters elicit an immune reaction?

- How do immunosuppressants interact with ABC transporters?

- How can exhausted membranes be restored with respect to ABC transporter activity?



ABC transporter containing membranes of particular interest are the trabecular meshwork in the eye, the blood-brain barrier (Alzheimer’s disease), membranes of the placenta (preeclampsia) and more.



Experimental work as well as reviews with a specific focus on molecular insights into the role of ABC transporters in immunology are accepted.

Please note that Dr Balazs Sarkadi is the partial owner and scientific advisor of Innocell Biotech Ltd. Also note that Dr Thomas Litman is a former employee of LEO Pharma A/S.