Toll-like receptors (TLRs) recognize conserved microbial structures expressed on a wide variety of pathogens including bacteria, viruses and protozoa. Activation of TLRs leads to induction of inflammatory responses that helps cells of the innate immune system to eliminate the pathogen but can also cause tissue damage and inflammatory diseases. After ligand recognition, TLRs transmit signals into the cell using their cytoplasmic domain called Toll-IL-1 receptor homology domain (TIR domain). All known TLR signaling adapters such as Myd88, TIRAP, TRIF and TRAM have C-terminal TIR domains that they use for interact with TIR domains of TLRs and induce pro-inflammatory cytokine production through activation of transcription factors such as NF-B, AP-1 and IRF proteins. We have recently identified a new TLR signaling adapter called BCAP that also has a TIR domain and participates in the TLR signaling pathway. The importance of BCAP is that it is critical to link TLRs to PI3 Kinase activation. PI3 Kinase regulates several outcomes of cellular behavior such as cell proliferation and cell survival. In addition we also find that BCAP is important to regulat inflammatory responses at least in part due to its ability to activate PI3 Kinase. Our preliminary studies have identified that BCAP plays an important role in regulating macrophage behavior and function and is critical for would healing and tissue repair following inflammatory damage. In addition we have also discovered that BCAP plays an essential role in regulating signaling downstream of IL-1 and IL-18 receptors. These two cytokine receptors also use TIR domains to signal and MyD88 is a known signaling adapter downstream of IL-1 family of receptors. Our data suggest that BCAP also plays a critical role downstream of IL-1 family of receptors in T cells and is important for regulating Th1 and Th17 cell differentiation. Our overall goals of this proposal are to elucidate the mechanisms by which BCAP regulates macrophage function in vivo during inflammation and also to understand the role of BCAP in regulating adaptive immunity. We propose two major aims in this proposal:
Aim1 will understand the role of BCAP in regulating gene expression in macrophages and the molecular mechanisms by which BCAP regulates inflammation.
Aim2 will investigate the role of BCAP in regulating dendritic cell function as well as the role of BCAP in IL-1 and IL-18 receptor signaling and its influence on T cell activation and differentiation. These studies will be critical to understand the role of BCAP and PI3K activation downstream of TLR/IL-1R super family of receptors and its importance in regulation of immune responses and inflammation.
Inflammation is a common response of the body in the event of infections as well as damage caused by injuries and noxious agents and the immune system uses several mechanisms to regulate inflammation as well as induce tissue repair mechanisms to heal injuries. We have recently discovered a new protein that participates in regulating inflammation caused by pathogens by modulating behavior of cells of the innate immune system. In this proposal, we intend to study the molecular mechanisms by which this novel protein regulates inflammation as well as its importance in activation of adaptive immune responses to pathogens.
