Contribution of phospholipase A2 enzymes in the homeostasis of the immune system

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BACKGROUND The immune system distinguishes the self from the non-self, preventing foreign organisms or other sort of insults from damaging the body. To ensure of its homeostasis, multiple mechanisms tightly regulate the immune system. It is now appreciated that a complex ecosystem of microorganisms, referred to as the microbiota, lives in symbiosis with mammals and modulates immune responses. In our NSERC program, we consider the role of bactericidal enzymes hydrolyzing phospholipids, called phospholipase A2 (PLA2), in the regulation of the immune system. HYPOTHESIS More specifically in this renewal application, we hypothesize that a secreted form of PLA2 (sPLA2), called sPLA2 group IIA (sPLA2-IIA), modulates key regulatory events of the immune system. We will use genetically engineered mice and we will scrutinize the impact of sPLA2-IIA expression on the immune system in mice. As sPLA2-IIA is a highly potent bactericidal enzyme constitutively expressed in mucosae, we will further consider its role on the regulation of immune homeostasis through its activity on the host's commensal microbes. AIMS To gain further insight into sPLA2 mechanism of action in immunity, we will investigate these following aims: 1. To characterize the impact of expression of sPLA2-IIA on immune homeostasis 2. To determine the effect of the expression of sPLA2-IIA on the normal flora in mice 3. To examine mechanism(s) by which sPLA2-IIA expression modulates the immune homeostasis SCIENTIFIC APPROACH The recent generation of mice deficient in specific sPLA2 isoforms provides a method for dissection of sPLA2 functions in vivo. We wish to highlight that a unique and powerful aspect of this proposal is the extensive array of tools' available for our analyses. These include a substantial number of genetically modified mouse strains, shot-gun based mass-spectrometry approach for the complete assessment of mouse microbiota, systems for large data analysis, a series of recombinant proteins (native and targeted mutations), methods for quantifying sPLA2 isoform expression and eicosanoid species. Importantly, the PI and his team of collaborators have extensive experience with sPLA2, microbiome and immunologic approaches. IMPACT Although sPLA2 enzymes have been known for at least two decades, the recent development of transgenic and knockout mice is just starting to permit the delineation of their contribution to physiology. This unique research program will reveal the role of a prominent sPLA2 enzyme in immunity, considering its role in the equilibrium of the microbiota.