Mouse Adrenal Macrophages Are Associated with Pre- and Postsynaptic Neuronal Elements and Respond to Multiple Neuromodulators

The adrenal medulla is packed with chromaffin cells, modified postganglionic sympathetic neurons that secrete the catecholamines, epinephrine and norepinephrine, during the fight-or-flight response. Sometimes overlooked is a population of immune cells that also resides within the gland but whose distribution and function are not clear. Here I examine the location of CD45+ hematopoietic cells in the mouse adrenal medulla and show the majority are F4/80+/Lyz2+ macrophages. These cells are present from early postnatal development and widely distributed. Anatomically they are associated with chromaffin cells, found aligned alongside synapsin-IR neuronal varicosities and juxtaposed to CD31-IR blood vessels. Using Lyz2cre-GCaMP6f mice to quantify calcium signaling in macrophages revealed these cells respond directly and indirectly to a wide variety of neuromodulators, including pre- and postganglionic transmitters and systemic hormones. Purinergic agonists, histamine, acetylcholine, and bradykinin rapidly and reversibly increased intracellular calcium. These results are consistent with a substantial resident population of innate immune cells in the adrenal medulla. Their close association with chromaffin cells and the preganglionic input suggests they may regulate sympatho-adrenal activity and thus the strength of the fight-or-flight response.