Chemokines and Anionic Phospholipids: New Binding Partners for Microbial Killing and Apoptotic Cell Clearance

Abstract Chemokines constitute a large family of small cytokines that regulate leukocyte migration in immunity and inflammation, some of which also have direct bacteria-killing properties. While the molecular mechanism by which chemokines kill bacteria remains poorly understood, chemokines mediate cell migration by interacting with cell surface glycosaminoglycans (GAGs) and G protein-coupled receptors (GPCRs). We have discovered that many chemokines interact with high affinity with anionic membrane phospholipids, including phosphatidylserine (PS) and cardiolipin (CL) which are selectively exposed on the membrane of apoptotic cells and apoptotic extracellular vesicles (ApoEV), and bacteria, respectively. This adds to GPCRs and GAGs a third class of cell surface binding site for chemokines and expands the scope of chemokine action to the biological niches occupied by PS and CL. For instance, we found that ApoEV induce phagocyte migration for apoptotic cell clearance by presenting PS-binding chemokines on the vesicle surface to GPCRs expressed by phagocytes. This is a novel PS-dependent mechanism for chemokine delivery by extracellular vesicles potentially relevant to other areas of immunology and indicates that chemokines may play a more prominent role in the removal of dying cells than previously reported. On the other hand, we discovered that only CL-binding chemokines are antimicrobial and that CL-deficient bacteria are resistant to chemokine treatment, indicating that chemokines kill bacteria by targeting CL on the bacterial membrane. In short, we have identified chemokines as the first family of soluble cytokines whose bioactivities can be regulated by direct interaction with membrane phospholipids. Supported by NIAID/NIH intramural research program