Our lab currently has three major ongoing lines of research:
Assessing the relevance of NFAT activation in innate immune and non-immune cells during the development of the inflammatory process.
Innate immune cells, particularly phagocytes, are equipped with a wide range of PRRs, and function as sentinels for the organism. Innate immunity is the most ancient form of response to pathogens, and the principle mechanisms of such immunity are evolutionarily conserved, from plants to humans. However, accumulating evidence suggests that transcription factors that appeared later during evolution also contribute to the development of the inflammatory process and to the regulation of innate immune responses in vertebrates. Nuclear Factor of Activated T cells (NFAT) is a family of transcription factors that was originally associated exclusively with adaptive immune cell activation; but we and others have now clearly established that, following exposure to inflammatory stimuli, NFAT family members are also activated in innate immune cells as well as in non-immune cells. We hypothesize that activation of the NFAT signaling pathway in innate immune cells (dendritic cells, mast cells, neutrophils) and non-immune cells (fibroblasts, endothelial cells) plays a fundamental role in conditioning the inflammatory process, and induces the formation of a protective long lasting immunity. To test this hypothesis, we have developed a unique nanoparticle-based tool that selectively inhibits NFAT activation in different cell types. We believe that a better understanding of the function of NFAT signaling in response to microbial - in particular during fungal infections or bacterial sepsis – and non-microbial – i.e. during transplant rejection – stimuli is a prerequisite for gaining insights into the molecular underpinnings of inflammatory processes and inflammation-driven immune memory formation.
Characterizing the diversification of signaling pathways that are triggered by PAMPs and DAMPs, and uncovering the cross-talk between these pathways.
The ability to distinguish self from non-self molecules is a fundamental feature of all forms of life, yet we do not fully understand how such a distinction is achieved. Charles Janeway Jr. was the first to propose that PRRs are essential for distinguishing self from non-self molecules. In fact, PRRs can directly or indirectly detect molecules that are common to broad classes of PAMPs. However, several recent studies report that specific PRRs recognize PAMPs as well as DAMPs, an observation that challenges the notion that these receptors can discriminate self/non-self molecules. We propose that innate immune receptors, together with their co-receptors, can distinguish self and non-self ligands, integrate this information (i.e., activate unique signaling pathways), and modulate the inflammatory process. The CD14-TLR4-MD-2 multi-receptor complex is one of the most studied PRR, and we have recently pioneered several projects on the signaling pathways that are activated downstream of this complex, in response to microbial ligands. We are now expanding this work to include endogenous ligands, with a focus on the capacity of DAMPs to modulate the inflammatory process elicited in response to PAMPs. We anticipate that this work will yield novel insights into the cross-talk between endogenous and exogenous ligands, and into how these pathways regulate the potency and efficacy of the inflammatory process. Our results should make vital contributions towards defining the processes that lead to the distractive and reparative phases of inflammation, and should have significant clinical consequences.
Determining the relevance of type III interferon (IFN) signaling for innate immune and non-immune cells.
Type III IFNs, also referred to as IFN lambdas, are a recently discovered class of IFNs. The dimeric receptor of type III IFNs is notable for its near-exclusive expression by mucosal epithelial cells: mice that are defective for type III IFN responsiveness are sensitive to challenge with mucosal, but not systemic, infections. Because type III IFNs are highly expressed by gut and lung epithelia after encounters with viruses or bacteria, most studies of type III IFNs have focused on the role of these molecules in epithelia. We and others have recently found that type III IFN receptor is also expressed on innate immune cells. We believe that type III IFNs regulate innate immune and non-immune cell functions, influence the responses elicited against microbial infections, and contribute to the development of inflammatory diseases such as IBDs and asthma. To test this hypothesis and uncover the mechanisms that support such roles, we are currently leveraging a conditional mouse model to test the relevance of type III IFN signaling in specific cell types during infection and/or during the development of inflammatory disease, both in vitro and in vivo.