There is increasing evidence that proton-coupled oligopeptide transporters (POTs) can transport bacterially-derived chemotactic peptides and, therefore, reside at the critical interface of innate immune responses and regulation. However, there is substantial contention regarding how these bacterial peptides access the cytosol to exert their effects, and which POTs are involved in facilitating this process. In this presentation, I will discuss the (sub)cellular expression and functional activity of POTs in macrophages derived from mouse bone marrow, and evaluate the effect of specific POT deletion on the production of inflammatory cytokines in wildtype, Pept2 knockout and Pht1 knockout mice. Specifically, we found that PEPT2 and PHT1 were highly expressed and functionally active in mouse macrophages, but PEPT1 was absent. The fluorescent imaging of muramyl dipeptide-rhodamine clearly demonstrated that PEPT2 was expressed on the plasma membrane of macrophages, whereas PHT1 was expressed on endosomal membranes. Moreover, both transporters could significantly influence the effect of bacterially-derived peptide ligands on cytokine stimulation, as shown by the reduced responses in Pept2 knockout and Pht1 knockout mice as compared to wildtype animals. Taken as a whole, our results point to PEPT2 (at plasma membranes) and PHT1 (at endosomal membranes) working in concert to optimize the uptake of bacterial ligands into the cytosol of macrophages, thereby enhancing the production of proinflammatory cytokines. This new paradigm offers significant insight into potential drug development strategies along with transporter-targeted therapies for endocrine, inflammatory and autoimmune diseases.
Upon completion, participants will be able to explain the methods by which bacterially-derived chemotactic peptides access the cytosol of macrophages.
Upon completion, participants will be able to identify the (sub)cellular expression of specific proton-coupled oligopeptide transporters in macrophages.
Upon completion, participants will be able to explain the mechanisms by which specific proton-coupled oligopeptide transporters influence the production of inflammatory cytokines in macrophages.