517.1 - Anionic membrane phospholipids: A New Class of Chemokine-Binding Site Important for both Apoptotic Cell Clearance and Antibiotic Activity by Chemokines - - Board: B161-162

Sergio Pontejo (National Institute of Allergy and Infectious Diseases), Philip Murphy (National Institute of Allergy and Infectious Diseases)

Chemokines are small cytokines that orchestrate immune cell migration by binding to cell surface glycosaminoglycans (GAGs) and activating G protein-couple receptors (GPCRs) expressed by leukocytes. We have discovered that chemokines selectively bind with high affinity to anionic membrane phospholipids, including phosphatidylserine (PS) and cardiolipin (CL). This adds to GPCRs and GAGs a third class of high affinity membrane binding site for chemokines and expands the scope of chemokine action to new areas of biology dictated by the specific biological niches occupied by their phospholipid binding partners. PS, for example, is usually restricted to the cytosolic face of the phospholipid bilayer of the plasma membrane of healthy eukaryotic cells, but it is flipped to the outer leaflet of the membrane of apoptotic cells and apoptotic extracellular vesicles (ApoEVs), where it acts as an eat-me signal recognized by phagocytes for apoptotic cell clearance. In this regard, we have recently demonstrated that ApoEVs generated in vivo from mouse thymus induce phagocyte migration using endogenous chemokines bound to the vesicle surface via PS. Our results indicate that PS-bound chemokines on ApoEVs may serve as find-me signals that recruit phagocytes toward apoptotic cells for the removal of dying cells. This is a new PS-dependent mechanism for chemokine delivery by extracellular vesicles. On the other hand, CL is absent in the plasma membrane of eukaryotic cells but it is a major and naturally exposed anionic phospholipid in the bacterial plasma membrane. As such, we have found that chemokines act as potent direct bacteria-killing agents by binding to bacterial CL. This finding identifies the molecular mechanism for antimicrobial action by chemokines and launch new avenues of research in antimicrobial therapies and bacteria-host interactions. In short, we have identified chemokines as the first example of a family of soluble cytokines whose functions are regulated by direct interaction with membrane phospholipids.

Support or Funding Information

National Institute of Allergy and Infectious Diseases-Intramural Research Program (grant number N/A) supported SMP and PMM.



Figure 1. A 'breadcrumb' model of phagocyte recruitment for apoptotic cell clearance. PS, phosphatidylserine; GPCR, G protein-coupled receptor.