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Virus-induced CXCL10-CXCR3 positive feedback loop via astrocytes is critical for maintaining chronic inflammatory lesions in HAM/TSP

  • Tomoo Sato1,
  • Hitoshi Ando1,
  • Utano Tomaru2,
  • Mari Yoshida3,
  • Atae Utsunomiya4,
  • Junji Yamauchi1,
  • Natsumi Araya1,
  • Naoko Yagishita1,
  • Ariella Coler-Reilly1,
  • Steven Jacobson5 and
  • Yoshihisa Yamano1Email author
Retrovirology201411(Suppl 1):O25

Published: 7 January 2014


Central Nervous SystemSpinal CordPeripheral Blood Mononuclear CellAstrocytomaChronic Inflammation

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a debilitating neurologic disorder characterized by chronic inflammation in the spinal cord. However, the precise mechanism by which chronic inflammatory lesions in HAM/TSP are formed and maintained has not been discovered. Since it is believed that chemokines play a central role in lymphocyte recruitment to sites of inflammation, we hypothesized that a positive feedback loop driven by chemokines may be responsible for the chronic inflammation in HAM/TSP. We aimed to determine the identity of these chemokines, where they are produced, and how they drive chronic inflammation in HAM/TSP. We found that HAM/TSP patients have extraordinarily high levels of the chemokine CXCL10 and an abundance of cells expressing the CXCL10-binding receptor CXCR3 in the cerebrospinal fluid. Histological analysis revealed that astrocytes are the main producers of CXCL10 in the spinal cords of HAM/TSP patients. Co-culture of human astrocytoma cells with CD4+ T-cells from HAM/TSP patients revealed that astrocytes produce CXCL10 in response to IFN-γ secreted by CD4+ T-cells. Chemotaxis assays results suggest that CXCL10 induces migration of peripheral blood mononuclear cells to the central nervous system (CNS) and anti-CXCL10 neutralizing antibody can disrupt this migration. In short, HTLV-1-infected cells in the CNS produce IFN-γ that induces astrocytes to secrete CXCL10 that recruits more infected cells to the area via CXCR3, constituting a Th1-centric positive feedback loop that results in chronic inflammation.

Authors’ Affiliations

Department of Rare Diseases Research, Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Aichi, Japan
Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Kagoshima, Japan
Viral Immunology Section, Neuroimmunology Branch, National Institutes of Health, Bethesda, USA


© Sato et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.