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Journal of Virology, January 2009, p. 522-539, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01210-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Modulation of Macrophage Infiltration and Inflammatory Activity by the Phosphatase SHP-1 in Virus-Induced Demyelinating Disease{triangledown}

George P. Christophi,1,2 Chad A. Hudson,1,2 Michael Panos,1 Ross C. Gruber,1 and Paul T. Massa1,2*

Department of Neurology,1 Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York2

Received 11 June 2008/ Accepted 29 October 2008

The protein tyrosine phosphatase SHP-1 is a crucial negative regulator of cytokine signaling and inflammatory gene expression, both in the immune system and in the central nervous system (CNS). Mice genetically lacking SHP-1 (me/me) display severe inflammatory demyelinating disease following inoculation with the Theiler's murine encephalomyelitis virus (TMEV) compared to infected wild-type mice. Therefore, it became essential to investigate the mechanisms of TMEV-induced inflammation in the CNS of SHP-1-deficient mice. Herein, we show that the expression of several genes relevant to inflammatory demyelination in the CNS of infected me/me mice is elevated compared to that in wild-type mice. Furthermore, SHP-1 deficiency led to an abundant and exclusive increase in the infiltration of high-level-CD45-expressing (CD45hi) CD11b+ Ly-6Chi macrophages into the CNS of me/me mice, in concert with the development of paralysis. Histological analyses of spinal cords revealed the localization of these macrophages to extensive inflammatory demyelinating lesions in infected SHP-1-deficient mice. Sorted populations of CNS-infiltrating macrophages from infected me/me mice showed increased amounts of viral RNA and an enhanced inflammatory profile compared to wild-type macrophages. Importantly, the application of clodronate liposomes effectively depleted splenic and CNS-infiltrating macrophages and significantly delayed the onset of TMEV-induced paralysis. Furthermore, macrophage depletion resulted in lower viral loads and lower levels of inflammatory gene expression and demyelination in the spinal cords of me/me mice. Finally, me/me macrophages were more responsive than wild-type macrophages to chemoattractive stimuli secreted by me/me glial cells, indicating a mechanism for the increased numbers of infiltrating macrophages seen in the CNS of me/me mice. Taken together, these findings demonstrate that infiltrating macrophages in SHP-1-deficient mice play a crucial role in promoting viral replication by providing abundant viral targets and contribute to increased proinflammatory gene expression relevant to the effector mechanisms of macrophage-mediated demyelination.

* Corresponding author. Mailing address: Department of Neurology, Upstate Medical University, State University of New York, 750 East Adams St., Syracuse, NY 13210. Phone: (315) 464-7606. Fax: (315) 464-6402. E-mail: massap{at}upstate.edu

{triangledown} Published ahead of print on 5 November 2008.

Journal of Virology, January 2009, p. 522-539, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01210-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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