Modulation of Sympatho-Adrenal Function by Tissue Resident Macrophages

点击翻译按钮获取中文摘要

PROJECT SUMMARY The autonomic nervous system is activated during the fight-or-flight response and functions to restore homeostasis. Autonomic activity can alter the function of every major organ system and regulates every significant physiological variable including blood pressure, body temperature, respiration rate and blood glucose levels. Dysregulation of autonomic function can have widespread consequences and is causally involved in the etiology of type I diabetes, hypertension, cancer and many dysautonomias. Thus understanding the control of autonomic output has implications for treating many common disease states. Most studies emphasize the role of the CNS and descending activity in determining autonomic function. However, recent work has shown that the autonomic and immune systems are functionally closely connected with bidirectional signaling pathways that regulate the output of both systems. One aspect of this interaction that is not well understood is the time scale over which this crosstalk can take place. The objective of the proposed study is to test the hypothesis that the release of the hormone epinephrine from sympathetic neurons (chromaffin cells) in the adrenal gland is regulated by a signaling pathway that involves a population of innate immune cells in the adrenal medulla. This idea is unconventional because epinephrine release is thought to be exclusively controlled by the strength of the neuronal preganglionic → chromaffin cell synapse. To test this idea we have two specific aims that we will address in mice using electrophysiological and chemogenetic approaches. In the first set of experiments we will test the hypothesis that changing the activity of adrenal macrophages is sufficient to rapidly change the strength of the preganglionic → chromaffin cell synapse by acting at a presynaptic locus. Our second specific aim is to test the hypothesis that adrenal macrophages are involved in regulating the ability of the chromaffin cells to secrete epinephrine. Because reliable epinephrine secretion requires an increase in the adrenal expression of tyrosine hydroxylase, we will also determine whether the chemogenetic stimulation of macrophages is sufficient to elevate the levels of this enzyme. Finally, we will test whether macrophages are involved in the fight-or-flight response in vivo and control the release of epinephrine into the systemic circulation. The current treatments for many forms of autonomic dysfunction are limited. If adrenal macrophages play a role in regulating sympatho-adrenal activity this would substantially widen the number of cellular and molecular targets that could be exploited to treat these clinically significant disorders.