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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.<\/jats:p>","DOI":"10.1523\/eneuro.0153-24.2025","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T18:50:23Z","timestamp":1738608623000},"page":"ENEURO.0153-24.2025","source":"Crossref","is-referenced-by-count":0,"title":["Mouse Adrenal Macrophages Are Associated with Pre- and Postsynaptic Neuronal Elements and Respond to Multiple Neuromodulators"],"prefix":"10.1523","volume":"12","author":[{"given":"Matthew D.","family":"Whim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"393","published-online":{"date-parts":[[2025,2,3]]},"reference":[{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0022-3565(25)12779-1","article-title":"Voltage and current clamp studies of muscarinic and nicotinic excitation of the rat adrenal chromaffin cells","volume":"255","author":"Akaike","year":"1990","journal-title":"J Pharmacol Exp Ther"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18642-y"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.29.17132"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.4","doi-asserted-by":"publisher","DOI":"10.1124\/mol.108.046904"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.5","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.1998.00349.x"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.18.9905"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24870-7"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01321-z"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.9","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1111\/all.13663","article-title":"Massive release of the histamine-degrading enzyme diamine oxidase during severe anaphylaxis in mastocytosis patients","volume":"74","author":"Boehm","year":"2019","journal-title":"Allergy"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.04.043"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.11","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(94)00869-8"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.12","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1161\/HYPERTENSIONAHA.117.09746","article-title":"Dysregulation of aldosterone secretion in mast cell-deficient mice","volume":"70","author":"Boyer","year":"2017","journal-title":"Hypertension"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.13","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/jnc.14149","article-title":"Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors","volume":"143","author":"Brindley","year":"2017","journal-title":"J Neurochem"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.14","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.104.6.1569"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.15","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1002\/cphy.c190003","article-title":"Chromaffin cells of the adrenal medulla: physiology, pharmacology, and disease","volume":"9","author":"Carbone","year":"2019","journal-title":"Compr Physiol"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.16","doi-asserted-by":"crossref","first-page":"ar92","DOI":"10.1091\/mbc.E24-02-0083","article-title":"A PACAP-activated network for secretion requires coordination of Ca2+ influx and Ca2+ mobilization","volume":"35","author":"Chen","year":"2024","journal-title":"Mol Biol Cell"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.17","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008942828960"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.18","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4997-09.2010"},{"key":"2025022510502164000_12.2.ENEURO.0153-24.2025.19","first-page":"173","article-title":"The innervation of the adrenal gland. 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