Atherosclerosis Peripheral Nervous System Crosstalk in Apolipoprotein E-deficient and Human Apolipoprotein E Isoform-specific Knock-in Mice

点击翻译按钮获取中文摘要

Peripheral inflammation is known to be sensed and affected by the peripheral nervous system (PNS). Atherosclerosis is a nonresolving inflammatory disease of arteries. However, there was no rational - until now - for studying the relation between atherosclerosis and the PNS, because the intima of arteries, i.e. the location where atherosclerosis pathology develops, is not innervated. Our group characterized artery tertiary lymphoid organs (ATLOs) in the aorta adventitia of Apoe-/- mice. Since the adventitia of all arteries is innervated, the discovery of ATLOs raised the possibility that ATLOs might interact with, be sensed, and affected by the PNS. We reasoned that studies into the PNS in the diseased aorta might possibly uncover atherosclerosis-PNS interactions. Unpublished data that I obtained over the past 4 years indeed reveal comprehensive neuroimmune interactions between diseased adventitia segments and the PNS. I observed: i) that adventitia segments adjacent to atherosclerotic plaques show markedly increased nerve axon density and that paraaortic ganglia (PAGs) and dorsal root ganglia (DRGs) show inflammatory infiltrates; ii) that axons directly interact with immune cells; and iii) that TLO-like structures emerge near PAGs and nerves. To understand the principal mechanisms of atherosclerosis-PNS crosstalk I propose in the research project detailed below to study the morphology and structure of TLOs and the inflammatory infiltrates in peripheral ganglia (Aim1); define roles of hyperlipidemia and of ApoE isoforms on neuroimmune crosstalks using humanized Apoe3 knock-in (KI) and Apoe4 KI mice (Aim2); determine which PNS constituents are involved in neuroimmune crosstalk (Aim3); construct transcript atlases through mapping of PAG mRNA microarrays (Aim4); analyze neurotransmitter receptors in Wt and Apoe-/- mice (Aim5); examine PNS-associated TLOs in human coronary artery adventitiae (Aim6).