TY - JOUR
T1 - Semaphorin4A and H-ferritin utilize Tim-1 on human oligodendrocytes
T2 - A novel neuro-immune axis
AU - Chiou, Brian
AU - Lucassen, Elisabeth
AU - Sather, Michael
AU - Kallianpur, Asha
AU - Connor, James
N1 - Funding Information:
This work was supported by the Department of Neurosurgery at Penn State College of Medicine and the G. M. Leader Family Research Fund. The San Diego HIV Neurobehavioral Research Center [HNRC] is supported by Center award P30MH062512 from NIMH. We also thank Drs. A. B. Madhankumar, Amanda Snyder, and David Degraff for their role in providing technical expertise and guidance. We are also grateful to the study participants who provided HIV+ CSF for these studies. The HNRC is affiliated with the University of California, San Diego, the Naval Hospital, San Diego, and the Veterans Affairs San Diego Healthcare System, and includes: Director: Robert K. Heaton, PhD, Co-Director: Igor Grant, MD; Associate Directors: J. Hampton Atkinson, MD, Ronald J. Ellis, MD, PhD, and Scott Letendre, MD; Center Manager: Thomas D. Marcotte, PhD; Jennifer Marquie-Beck, MPH; Melanie Sherman; Neuromedical Component: Ronald J. Ellis, MD, PhD (P. I.), Scott Letendre, MD, J. Allen McCutchan, MD, Brookie Best, PharmD, Rachel Schrier, PhD, Debra Rosario, MPH; Neurobehavioral Component: Robert K. Heaton, PhD (P. I.), J. Hampton Atkinson, MD, Thomas D. Marcotte, PhD, Mariana Cherner, PhD, David J. Moore, PhD, Erin Morgan, PhD, Matthew Dawson; Neuroimaging Component: Christine Fennema-Notestine, PhD (P. I.), Monte S. Buchsbaum, MD, John Hesselink, MD, Sarah L. Archibald, MA, Gregory Brown, PhD, Richard Buxton, PhD, Anders Dale, PhD, Thomas Liu, PhD; Neurobiology Component: Eliezer Masliah, MD (P. I.), Cristian Achim, MD, PhD; Neurovirology Component: David M. Smith, MD (P. I.), Douglas Richman, MD; International Component: J. Allen McCutchan, MD, (P. I.), Mariana Cherner, PhD; Developmental Component: Cristian Achim, MD, PhD; (P. I.), Scott Letendre, MD; Participant Accrual and Retention Unit: J. Hampton Atkinson, MD (P. I.), Jennifer Marquie-Beck, MPH; Data Management and Information Systems Unit: Anthony C. Gamst, PhD (P. I.), Clint Cushman; Statistics Unit: Ian Abramson, PhD (P. I.), Florin Vaida, PhD (Co-PI), Anya Umlauf, MS, Bin Tang, MS. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the United States Government.
Funding Information:
This work was supported by the Department of Neurosurgery at Penn State College of Medicine and the G. M. Leader Family Research Fund. The San Diego HIV Neurobehavioral Research Center [HNRC] is supported by Center award P30MH062512 from NIMH. We also thank Drs. A. B. Madhankumar, Amanda Snyder, and David Degraff for their role in providing technical expertise and guidance. We are also grateful to the study participants who provided HIV1 CSF for these studies. The HNRC is affiliated with the University of California, San Diego, the Naval Hospital, San Diego, and the Veterans Affairs San Diego Healthcare System, and includes: Director: Robert K. Heaton, PhD, Co-Director: Igor Grant, MD; Associate Directors: J. Hampton Atkinson, MD, Ronald J. Ellis, MD, PhD, and Scott Letendre, MD; Center Manager: Thomas D. Marcotte, PhD; Jennifer Marquie-Beck, MPH; Melanie Sherman; Neuromedical Component: Ronald J. Ellis, MD, PhD (P. I.), Scott Letendre, MD, J. Allen McCutchan, MD, Brookie Best, PharmD, Rachel Schrier, PhD, Debra Rosario, MPH; Neurobehavioral Component: Robert K. Heaton, PhD (P. I.), J. Hampton Atkinson, MD, Thomas D. Marcotte, PhD, Mariana Cherner, PhD, David J. Moore, PhD, Erin Morgan, PhD, Matthew Dawson; Neuroimaging Component: Christine Fennema-Notestine, PhD (P. I.), Monte S. Buchsbaum, MD, John Hesselink, MD, Sarah L. Archibald, MA, Gregory Brown, PhD, Richard Buxton, PhD, Anders Dale, PhD, Thomas Liu, PhD; Neurobiology Component: Eliezer Masliah, MD (P. I.), Cristian Achim, MD, PhD; Neurovirology Component: David M. Smith, MD (P. I.), Douglas Richman, MD; International Component: J. Allen McCutchan, MD, (P. I.), Mariana Cherner, PhD; Developmental Component: Cristian Achim, MD, PhD; (P. I.), Scott Letendre, MD; Participant Accrual and Retention Unit: J. Hampton Atkinson, MD (P. I.), Jennifer Marquie-Beck, MPH; Data Management and Information Systems Unit: Anthony C. Gamst, PhD (P. I.), Clint Cushman; Statistics Unit: Ian Abramson, PhD (P. I.), Florin Vaida, PhD (Co-PI), Anya Umlauf, MS, Bin Tang, MS. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the United States Government.
Publisher Copyright:
© 2018 Wiley Periodicals, Inc.
PY - 2018/7
Y1 - 2018/7
N2 - Deficiency of trophic factors relating to the survival of oligodendrocytes, combined with direct interactions with the immune system, are favored paradigms that are increasingly implicated in demyelinating diseases of the central nervous system. We and others have previously shown that Sema4A and H-ferritin interact through the T-cell immunoglobulin and mucin domain (Tim-2) receptor in mice. H-ferritin has been identified as the iron delivery protein for oligodendrocytes, whereas Sema4A causes a direct cytotoxic effect. However, the expression of Tim-2 has not been detected in humans. Here, we demonstrate that, similar to rodents, human oligodendrocytes undergo apoptosis when exposed to Sema4A and take up H-ferritin for meeting iron requirements and that these functions are mediated via the Tim-1 receptor. Moreover, we also demonstrate the ability of H-ferritin to block Sema4A-mediated cytotoxicity. Furthermore, we show in a series of pilot studies that Sema4A is detectable in the CSF of multiple sclerosis patients and HIV-seropositive persons and can induce oligodendrocyte cell death. Together, these results identify a novel iron uptake mechanism for human oligodendrocytes and a connection between oligodendrocytes and the immune system.
AB - Deficiency of trophic factors relating to the survival of oligodendrocytes, combined with direct interactions with the immune system, are favored paradigms that are increasingly implicated in demyelinating diseases of the central nervous system. We and others have previously shown that Sema4A and H-ferritin interact through the T-cell immunoglobulin and mucin domain (Tim-2) receptor in mice. H-ferritin has been identified as the iron delivery protein for oligodendrocytes, whereas Sema4A causes a direct cytotoxic effect. However, the expression of Tim-2 has not been detected in humans. Here, we demonstrate that, similar to rodents, human oligodendrocytes undergo apoptosis when exposed to Sema4A and take up H-ferritin for meeting iron requirements and that these functions are mediated via the Tim-1 receptor. Moreover, we also demonstrate the ability of H-ferritin to block Sema4A-mediated cytotoxicity. Furthermore, we show in a series of pilot studies that Sema4A is detectable in the CSF of multiple sclerosis patients and HIV-seropositive persons and can induce oligodendrocyte cell death. Together, these results identify a novel iron uptake mechanism for human oligodendrocytes and a connection between oligodendrocytes and the immune system.
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UR - http://www.scopus.com/inward/citedby.url?scp=85042087163&partnerID=8YFLogxK
U2 - 10.1002/glia.23313
DO - 10.1002/glia.23313
M3 - Article
C2 - 29457657
AN - SCOPUS:85042087163
VL - 66
SP - 1317
EP - 1330
JO - GLIA
JF - GLIA
SN - 0894-1491
IS - 7
ER -
