Receptor-independent, lipid dependent mechanism of Syk kinase activation in dendritic cells (134.71)

Abstract

The binding of antigens to professional antigen-presenting cells (APCs), particularly dendritic cells (DCs), is essential for immune activation. Previously, it was shown that uric acid crystals, the causative agent of gout, were released from dying and injured cells as a "danger signal" to initiate a robust adaptive immune response. But how uric acid crystals lead to APC activation at a molecular level is unknown. Using atomic force microscopy (AFM) to analyze single cell activation in real time, we demonstrate that uric acid crystals directly bind cellular membranes, particularly cholesterol components, with very high affinity. Binding is dependent on intracellular Syk-kinase and PI3-kinase signaling and is independent of extracellular protein receptors. These findings suggest a mechanism that activates the immune system without specific cell surface protein receptors and presents a testable hypothesis for inflammation to materials without evolutionarily sensible receptors such as materials produced post-industrially. This research has applications in vaccine development, biomaterials, inflammation, and crystal-associated arthropathies.