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Microglia in the Ear in Health and Disease

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THE Newsletter of the NIDCD National Temporal Bone, Hearing and Balance Pathology Resource Registry Microglia in the ear in health Winter 2015 Vol. 23, No. 1 and disease Jennifer O’Malley, Felipe Santos, M.D., and Michael McKenna, M.D. Department of Otolaryngology, Harvard Medical School, Massachusets Eye and Ear, Boston, MA CONTENTS icroglia are a class of cells present in the central nervous system. Tey Featured Research represent 10 percent of the total cells in the central nervous system (CNS) Microglia in the ear in health but vary in density by region1,2,3. Tey are important in the development and disease .....................................1 and maintenance of organ function and are the sensor and efector cells Light-Sheet Microscopy for of the innate immune system. Tey have also been shown to play a role in Imaging Whole Cochleas ................5 Mthe development of several neurodegenerative diseases including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Parkinson’s disease4. Registry News Upcoming Event .............................4 Spiral We have demonstrated that these cells are present in abundance in the human inner Otopathology Mini-Travel Ligament Fellowship ......................................7 ear in a variety of locations, including the spiral ligament, (fgure 1), stria vascularis, Order form for Temporal Bone (fgure 2), osseous spiral lamina, (fgure 3), Donaton Brochures .......................8 spiral (fgure 4) and Scarpa’s ganglions, and within the auditory (fgure 5) and vestibular nerves5. Almost certainly, MISSION STATEMENT they play a role in the maintenance of The NIDCD Natonal Temporal Bone, normal function of the inner ear. Based Hearing and Balance Pathology Resource on a growing body of data from other Registry was established in 1992 by the organ systems, including the CNS, we Natonal Insttute on Deafness and Other hypothesize a fundamental role in the Communicaton Disorders (NIDCD) of the maintenance of cochlear homeostasis and Natonal Insttutes of Health to contnue in the development of otologic disease, and expand upon the former Natonal including several disorders that have Temporal Bone Banks (NTBB) Program. been considered heretofore idiopathic, The Registry promotes research on including sudden hearing loss, auto- hearing and balance disorders and serves immune inner ear disease, Ménière’s as a resource for the public and the continued on page 2 scientfc community about research on the pathology of the human auditory Figure 1. Three ramifed cells staining positve for Iba1, a marker known to be specifc for microglia, and vestbular systems. are from the area of the spiral ligament. The cells were from the cochleae of two diferent male individuals ages 70 and 88 with no known otologic issues other than those associated with age. Stria Vascularis and Otic Capsule THE DIRECTORS Joseph B. Nadol, Jr., M.D. Michael J. McKenna, M.D. Steven D. Rauch, M.D. Joseph C. Adams, Ph.D. Figure 2. Iba1 positve cells in the stria were present around blood vessels (BV) and within the SCIENTIFIC ADVISORY COUNCIL intermediate cell layer. There were microglia/macrophages that extended from the spiral ligament Newton J. Coker, M.D. into the bone of the otc capsule (*). A,B, and E are from a 58 year old male individual with normal hearing for age. C and D are from the 70 year old individual in Figure 1. Howard W. Francis, M.D. Marlan R. Hansen, M.D. Raul Hinojosa, M.D. Cochlea Akira Ishiyama, M.D. Herman A. Jenkins, M.D. Elizabeth M. Keithley, Ph.D. Robert I. Kohut, M.D. Fred H. Linthicum, Jr., M.D. Joseph B. Nadol, Jr., M.D. Michael Paparella, M.D. Jai H. Ryu, Ph.D. Isamu Sando, M.D., D.M.Sc. P. Ashley Wackym, M.D. Charles G. Wright, Ph.D. COORDINATOR Nicole Pelleter ADMINISTRATIVE STAFF Kristen Kirk-Paladino Figure 3. Microglia/macrophages were present in the osseous spiral lamina (OSL) and limbus spiralis Tammi N. King (LS). Those demonstrated here have a ramifed morphology. There were ofen amoeboid cells Garyfallia Pagonis present along Reissner’s membrane (RM) on the scala vestbuli side. One inner hair cell (IHC) can also be seen here. This specimen is from an 82 year old female with no known otologic disease EDITORS other than changes due to age. General: Suzanne Day Medical: Joseph B. Nadol, Jr., M.D. disease and cochlear otosclerosis. As such, otic microglia represent a new potential target DESIGNER for treatment and possible prevention of a host of otologic disorders with drugs that have Garyfallia Pagonis been developed for the treatment of other disorders of similar etiology. NIDCD Natonal Temporal Bone, Until recently, microglia within the inner ears of humans could not be appreciated or Hearing and Balance Pathology evaluated. Improvements in the immunostaining of archival human temporal bones6, 7 Resource Registry have made possible the identifcation of abundant microglia throughout the inner ear. Massachusets Eye and Ear Tese cells are morphologically similar to microglia in the CNS and to date express 243 Charles Street some of the same specifc markers. Boston, MA 02114 What are microglia? (800) 822-1327 Toll-Free Voice (617) 573-3711 Voice Microglia are derived from erythromyeloid progenitor cells that migrate into the CNS (617) 573-3838 Fax during embryologic development. Tese progenitors develop lineage-specifc gene expression and mature into microglia8, 9. Microglia play multiple roles in homeostasis. Email: [email protected] Residing in close proximity to synapses and dendrites, microglia are fundamental in Web: www.tbregistry.org axonal development and pruning. Tey can respond to changes in neuronal activity and 10, 11, 12 In the Summer 2015 issue of The Registry on can even modulate the fring pattern of neurons . Microglia are phagocytic and in page 5, Dr. Kumiko Hosokawa’s name is misspelled. The editors of The Registry regret this error. 2THE Vol. 23.1 | Winter 2015 development they can clear neurons that have undergone Spiral Ganglion apoptosis13 and they can also directly instruct neurons to undergo apoptosis14, 15, 16. With maturation in the CNS, microglia become relatively inconspicuous by standard histology. Te cell bodies contract and they develop long highly motile processes that participate in autocrine and paracrine signaling with cells in their immediate environment. Tese motile processes are constantly moving and sampling the surroundings17. Tey possess specifc receptors3 for cellular injury and invading pathologic organisms. Tese stimuli result in a rapid response during which microglia enlarge with lysosomal cytoplasmic components, retraction of the microprocesses, and the assumption of a motile tissue macrophage morphology and function. Tis process of microglial activation can be associated with the recruitment of circulating monocytes and other infammatory cells. In addition to their ability to respond to local insults, their function is highly modulated by circulating cytokines including those liberated by distant infammation. Microglial processes are also intimately associated with the microvasculature and control vascular permeability, extracellular fuid volume and composition. In the CNS, aberration in the activation of Figure 4. Microglial cells were present around spiral ganglion cells microglia leads to an amplifed infammatory state that can (SpGC) in a 70 year old male (same ear as Figure 1). Most of those shown here have a ramifed morphology. result in neurotoxicity implicating their role in virtually every neurodegenerative disorder. It seems likely that given the abundance of microglia in the ear that similar biological process Animal models and what they ofer are occurring within the ear in some individuals with auditory Perhaps the most fundamental question concerns the role of and vestibular dysfunction. microglia in cochlear and vestibular physiology. Do they solely serve as sentries of the innate immune system or do they play Te challenge lies in defning the role of microglia in human other regulatory roles in normal cochlear function? To answer otopathology. Animal models, although essential, have these questions, investigators have focused eforts on depleting signifcant and fundamental diferences from human disease microglia and determining organ specifc efects. Until recently processes. Tese diferences have been an impediment to the these studies were confounded by side efects of the depletion development of efective treatment as successful approaches in methods. Te recent development of a drug that inhibits the mice have often been unsuccessful in humans with disorders 18 receptor of Colony Stimulating Factor 1 (CSF R1) has been of the CNS. shown to deplete 99% of microglia in the CNS and ear. When Approach to human otopathology the drug is discontinued, the microglial population rapidly regenerates from progenitor stem cells which reside within To understand the role of microglia in human otopathology, it the CNS and presumably within the ear19. Remarkably, these is necessary to characterize what aspects of processing archival mice remain healthy despite microglial depletions for extended specimens impact our ability to immunostain these cells. Next, periods of time. With such models, it is possible to determine it will be necessary to characterize microglial density and the role of microglia in modulating the response to trauma, staining patterns in normal individuals over all age ranges. Any including noise. Such models will allow us to understand assessment of pathological cases will require this normative data.
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