Over-expression of Chitotriosidase Modulates Macrophage Function and Progression of Atherosclerosis in Hyperlipidemic, LDLr-/- Mice

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Abstract/Project summary: It is estimated that cardiovascular disease (CVD) accounts for nearly 1 of every 3 deaths in the United States (30.8%, American Heart Association, 2013). Atherosclerosis is the leading cause of CVD, and inflammation and dysregulation of the innate immune response are critical processes in all phases of disease progression. Macrophages are the predominant innate immune cell type in atheromatous plaques and play a major role in disease progression. Macrophage chitotriosidase-1 (CHIT1) is a mammalian chitinase that is produced, stored, and secreted by activated macrophages as part of the innate immune response against exogenous, chitin-containing pathogens. Previously published work from our laboratory revealed that Inhibition of chitinase promotes atherosclerosis in hyperlipidemic mice. Our preliminary data suggest that over-expression of CHIT1 results in modulation of macrophage function upon stimulation with both pro-inflammatory and anti-inflammatory mediators. Alterations in lipid handling properties of macrophages was also observed upon incubation with oxidized-LDL and acetylated-LDL. Despite the absence of an endogenous mammalian substrate, CHIT1 appears to have cytokine-like signaling functions independent of its enzymatic activity. These findings led us to the following central hypothesis: Macrophage over-expression of CHIT1 will attenuate the development of atherosclerosis by limiting inflammation and lipid accumulation. The aims that I propose to test this hypothesis are: Aim 1) Investigate the effect of CHIT1 over-expression on inflammatory response in macrophages, Aim 2) Determine whether CHIT1 over-expression modulates lipid accumulation in macrophages, and Aim 3) Explore the effects of CHIT1 over-expression in atherosclerosis mouse model. We have developed an LDLR-/-/ CHIT1 over-expressing mouse model (CHIT1-Tg) which will allow us to study the effects of CHIT1 over- expression on atherosclerosis in vivo. Bone marrow-derived macrophages from LDLR-/- /CHIT1-Tg and CRE-, littermate controls will be used to determine whether CHIT1 augments inflammation and lipid uptake by macrophages in vitro. Achieving these aims will allow us to elucidate the relationship between CHIT1 and atherosclerosis as it pertains to sterile inflammation, leukocyte migration, and lipid handling by macrophages; all critical aspects of therapeutic intervention and potential modes of disease cessation.