Ivan Zanoni laboratory studies innate immune cell biology as a means of understanding the earliest events that initiate immunity to infection or drive the development of immune-mediated diseases. He focused primarily on the study of Pattern Recognition Receptor (PRR) signaling pathways. PRRs initiate all immune responses and activate a network of transcription factors that orchestrate the inflammatory response. The organizing principles that govern PRR signaling are largely unknown and their elucidation will likely answer several fundamental questions about the pathophysiological development of the inflammatory process. His work established the first example of a cellular response to bacterial lipopolysaccharide (LPS) that does not depend on Toll-like Receptor (TLR)4, the prototype of the TLRs that are the best characterized family of PRRs. It has long been dogma that signaling via TLR4 is the only means by which mammalian cells respond to LPS. Ivan Zanoni uncovered that CD14 controls the LPS-induced endocytosis of TLR4, a process that is critical for the signaling functions of this receptor in numerous mammalian cell types. He also found that dendritic cells respond to LPS in a TLR4-independent manner that is important for regulating the activation of the Nuclear Factor of Activated T cells (NFAT). This work blurred the line between innate and adaptive immunity, and documented that NFAT operates in cells of both types of immunity. His findings that TLR4-independent LPS response pathway exists and that CD14 has autonomous signaling capacity open new perspectives on the study of LPS-driven inflammatory diseases and, in general, on the potential of co-receptors to modify and integrate the immune responses elicited by their cognate receptor. Goals of Dr. Zanoni’s research include: Understanding the molecular mechanisms that govern the cross-talk between co-receptors and their cognate receptors; Understanding how NFAT activation in innate immune cells regulates the inflammatory process; Understanding how PRRs signaling contributes to the development of inflammatory diseases and metabolic disorders.