Innate Immune Mechanisms and TLRs in Bacterial Ligand-Induced Arteritis

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DESCRIPTION (provided by applicant): Cellular and molecular mechanisms mediating inflammatory vascular diseases are not well understood. Our previous work has centered on the role of innate immune signaling via Toll-like receptors (TLRs) in inflammatory diseases such as atherosclerosis and arteritis. We reported that injection of cell wall extracts from L. casei (LCCWE) cause coronary arteritis in mice via a TLR2- and MyD88-dependent mechanism, but cell wall extracts from the closely related species L. paracasei do not. Building on this work, our recent preliminary studies now indicate that LCCWE does not induce coronary arteritis in RAG1-/- mice, which lack both T cells and B cells, but does induce lesions in mice that lack only B cells. These important findings now implicate adaptive immune mechanisms (particularly T cells) in addition to innate immune mechanisms (TLR signaling and dendritic cells [DCs]) in the mechanism of LCCWE-induced immune arteritis. Here we propose studies to elucidate cellular and molecular immune mechanisms contributing to bacterial antigen-induced coronary arteritis in mice. Combining available published data with our recent preliminary studies, we propose studies with 3 Specific Aims to test the hypothesis for an expanded model of arteritis that involves both innate and adaptive immunity, that centrally involves both TLR-2 and MyD88-dependent DC and T cell activation. Aim 1 will determine whether DCs participate in LCCWE-induced coronary arteritis in vivo and will evaluate how TLR signaling in DCs affects development of the pathology. We will quantify mature DCs at sites of coronary arteritis at different times and test whether DCs are essential for development of coronary arteritis by depleting DCs prior to injection of LCCWE using an established transgenic mouse model that produces temporary depletion of CD11c+ DCs (CD11c- DTR-GFP Tg+ mice). We will test whether transgenic mice expressing MyD88 only in CD11c+ DCs (in MyD88-null background) develop LCCWE-induced coronary arteritis. Aim 2 will test whether TLR2- and/or MyD88-dependent signaling in hematopoietic cells, in non-hematopoietic cells, or both are essential for development of bacterial antigen-induced immune arteritis. We will create and test chimeras that express TLR2 or MyD88 only in bone marrow-derived cells or only in the rest of the animal. Aim 3 will examine the role of the T cells and T cell subsets in LCCWE-induced coronary arteritis model using various KO mice. Significance: These studies should provide innovative mechanistic insights into the cellular and molecular underpinnings of various forms of immune-mediated arteritis, including the coronary arteritis seen in children with Kawasaki Disease. PUBLIC HEALTH RELEVANCE: Innate immune responses play a role in Bacterial cell wall extract-induced coronary arteritis in a mouse model. Kawasaki Disease is a vasculitis involving children and results in over 20% incidence of developing coronary arteritis and aneurysms. The role of bacterial infections in vasculitis and immune arteritis and the molecular mechanisms involved in this process are not well-understood. The major goal of this application is to understand the molecular mechanisms and the role of innate and adaptive immunity that explain exactly how certain bacterial infections can lead to immune vasculitis and coronary arteritis using a mouse model. The successful completion of the proposed studies may allow us to develop novel treatment or preventive approaches to infection-mediated development of vasculitis and immune arteritis.