CNS Inflammation and Bone Marrow Neuropathy in Type 1 Diabetes

• Published in: The American journal of pathology Vol. 183; no. 5; pp. 1608 - 1620
• Main Authors: Hu, Ping, Thinschmidt, Jeffrey S., Yan, Yuanqing, Hazra, Sugata, Bhatwadekar, Ashay, Caballero, Sergio, Salazar, Tatiana, Miyan, Jaleel A., Li, Wencheng, Derbenev, Andrei, Zsombok, Andrea, Tikhonenko, Maria, Dominguez, James M., McGorray, Susan P., Saban, Daniel R., Boulton, Michael E., Busik, Julia V., Raizada, Mohan K., Chan-Ling, Tailoi, Grant, Maria B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2013; American Society for Investigative Pathology
• Subjects: Animals; Bone Marrow - drug effects; Bone Marrow - innervation; Bone Marrow - pathology; Central Nervous System - drug effects; Central Nervous System - metabolism; Central Nervous System - pathology; Cytokines - metabolism; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - pathology; Enzyme-Linked Immunosorbent Assay; Green Fluorescent Proteins - metabolism; Hematopoiesis - drug effects; Herpesvirus 1, Suid - drug effects; Herpesvirus 1, Suid - physiology; Humans; Inflammation - complications; Inflammation - metabolism; Inflammation - pathology; Intercellular Signaling Peptides and Proteins - metabolism; Male; Mice; Mice, Inbred C57BL; Microglia - drug effects; Microglia - metabolism; Microglia - pathology; Minocycline - pharmacology; Models, Biological; Monocytes - drug effects; Monocytes - metabolism; Monocytes - pathology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neurotransmitter Agents - metabolism; Pathology; Proto-Oncogene Proteins c-fos - metabolism; Rats; Rats, Wistar; Regular; Sympathetic Nervous System - drug effects; Sympathetic Nervous System - metabolism; Sympathetic Nervous System - pathology
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.1016/j.ajpath.2013.07.009

By using pseudorabies virus expressing green fluorescence protein, we found that efferent bone marrow–neural connections trace to sympathetic centers of the central nervous system in normal mice. However, this was markedly reduced in type 1 diabetes, suggesting a significant loss of bone marrow innervation. This loss of innervation was associated with a change in hematopoiesis toward generation of more monocytes and an altered diurnal release of monocytes in rodents and patients with type 1 diabetes. In the hypothalamus and granular insular cortex of mice with type 1 diabetes, bone marrow–derived microglia/macrophages were activated and found at a greater density than in controls. Infiltration of CD45+/CCR2+/GR-1+/Iba-1+ bone marrow–derived monocytes into the hypothalamus could be mitigated by treatment with minocycline, an anti-inflammatory agent capable of crossing the blood-brain barrier. Our studies suggest that targeting central inflammation may facilitate management of microvascular complications.