ADAP Y571 Phosphorylation Is Required to Prime STAT3 for Activation in TLR4-Stimulated Macrophages

Abstract Adhesion and degranulation–promoting adapter protein (ADAP), originally identified as an essential adaptor molecule in TCR signaling T cell adhesion, has emerged a critical regulator innate immune cells such macrophages; however, its role macrophage polarization inflammatory responses remains unknown. In this study, we show that ADAP plays TLR4-mediated mouse via modulation of STAT3 activity. Macrophages from ADAP-deficient mice exhibit enhanced M1 polarization, expression proinflammatory cytokines capacity inducing Th1 responses, but decreased levels anti-inflammatory response to TLR4 activation by LPS. Furthermore, overexpression enhances, whereas loss reduces, the LPS-mediated phosphorylation activity STAT3, suggesting acts coactivator function. function mostly depends on tyrosine at Y571 motif YDSL induced Mutation F severely impairs stimulating effect ability inhibit M1-like TLR4-activated macrophages. Moreover, interacts with renders macrophages less sensitive IL-6 stimulation for phosphorylation. Collectively, our findings revealed additional layer regulation plasticity whereby is required prime TLR4-stimulated