Research in our laboratory focuses on the regulation of the innate immune response to pathogens with an emphasis on macrophages and dendritic cells. Macrophages and dendritic cells are distributed throughout the body where they are poised to detect pathogens and to subsequently alert the immune system to the presence of infection through the production of inflammatory mediators. The production of inflammatory mediators, such as tumor necrosis factor (TNF) and other pro-inflammatory cytokines, is tightly regulated. Although these important cytokines are beneficial to the host for pathogen clearance, they can be detrimental if unchecked. This can be seen in septic shock as well as in autoimmune disorders such as rheumatoid arthritis.
Macrophages and dendritic cells recognize pathogens by a variety of cell surface and intracellular receptors termed pattern recognition receptors, including the family of Toll-like receptors (TLR). We study how signaling through pattern recognition receptors results in the appropriate inflammatory response by macrophages and dendritic cells. We are particularly interested in proteins that inhibit signaling through pattern recognition receptors, providing an essential check to the inflammatory response. These studies will not only help elucidate how inflammatory cytokine production is regulated during infection, but will potentially give insights in how to manipulate the innate immune system to achieve more efficient elimination of pathogens and to regulate the inflammatory response during disease. This is a topic of significance in the development of vaccines and immunomodulatory drugs to prevent and treat infections as well as to regulate inflammatory diseases.
Two proteins we study in this regard are TREM-2 and DAP12, which together make up a receptor signaling complex expressed on macrophages and dendritic cells. TREM-2 is an Ig superfamily receptor without its own signaling capacity that associates with DAP12, an ITAM (immunoreceptor tyrosine-based activation motif)-containing transmembrane signaling adapter, to transduce signals. Macrophages lacking DAP12 or TREM-2 have increased inflammatory cytokine production after stimulation through TLRs demonstrating their function in inhibiting TLR responses. This was a surprising function for an activating receptor complex and we are studying several aspects of this system. This includes the signal transduction, the receptor-ligand interactions and the in vivo biology of TREM-2/DAP12 inhibition of TLR-based inflammatory responses.