Endogenous Activators of Inflammation in Insects and Mammals

The second half of the Balzan Prize to Jules Hoffmann and Bruce Beutler will be split evenly between two institutions, 50% to the CNRS Unit 9022 of the Institute of Molecular and Cellular Biology in Strasbourg and 50% to the Department of Genetics of the Scripps Research Institute in La Jolla. It will be used for joint efforts regarding the establishment of a model of inflammation in insects and mammals. In fact, the two scientists will hire young researchers and supervise research work in their respective laboratories, which will lead to a comparative analysis of the IMD (fly) and TNF-TLR (mouse) proinflammatory, signalling pathways in infection and development.

Inflammation is a major health problem in humans. Experimental studies on mice, performed in the early 1980s by Beutler and colleagues, established that the cytokine TNF (tumor necrosis factor) is a central player of inflammation. TNF also controls essential steps of development (namely, the ontogeny of secondary lymphoid organs). In the fly, a regulatory network similar to that initiated by the cytokine TNF was discovered by the Hoffmann laboratory with a series of brilliant studies that appeared from the end of the 1980s onwards. It was named IMD and shown to control the defence against some bacterial infections. One of the crucial phases was the publication in Cell in 1996, which showed that the gene encoding a membrane receptor called Toll (already known for its role in the development of Drosophila) was critical for the release of the fly’s defences against a fungal infection. The genes involved in the cascade that leads from the receptor Toll to the production of antifungal and antibacterial peptides (for Gram positive bacteria) as well as the mechanisms fighting Gram negative bacteria were subsequently identified by the Strasbourg team. These findings were followed by the discovery of TLR (Toll Like Receptors) in mammals, which are counterparts of the Toll receptor in insects. Bruce Beutler was the first to understand the defensive function of the mammalian TLRs and their relationship to the induction of TNF. The IMD pathway has its own sensing mechanism, where the TNF pathway does not. Rather, the TNF pathway may be viewed as a distal extension of the TLR pathway in mammals. In fact, the two pathways should be seen as one, with the TLRs (homologous to Toll) serving as the sensors.

Our knowledge of the IMD pathway is fragmentary, and with the second half of his Balzan Prize, Hoffmann’s aim is to provide an in-depth analysis of the proteins involved in this pathway, their interactions and functions. This will be done through a new and powerful proteomic analysis based on in vitro experiments performed with immuno-responsive cell lines. Most of the studies will be performed in association with the Beutler laboratory, which has a major interest in inflammation and in the cytokine TNF. The research in Beutler’s laboratory will concentrate on endogenous TLR activators created by mutations of proteins that normally lack activating potential.