title: Modulation of macrophage infiltration and inflammatory activity by the phosphatase SHP-1 in virus-induced demyelinating disease.
abstract: 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 (CD45(hi)) CD11b(+) Ly-6C(hi) 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.
authors.affiliation: Department of Neurology, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: George P
authors.initials: GP
authors.lastname: Christophi
authors.forename: Chad A
authors.initials: CA
authors.lastname: Hudson
authors.forename: Michael
authors.initials: M
authors.lastname: Panos
authors.forename: Ross C
authors.initials: RC
authors.lastname: Gruber
authors.forename: Paul T
authors.initials: PT
authors.lastname: Massa
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000032:analysis; D039481:CD11b Antigen / Q000032:analysis; D002490:Central Nervous System / Q000276:immunology*; D004002:Clodronic Acid / Q000494:pharmacology; D020869:Gene Expression Profiling; D007155:Immunologic Factors; D007249:Inflammation / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D047589:Leukocyte Reduction Procedures; D008264:Macrophages / Q000737:chemistry / Q000276:immunology* / Q000821:virology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D011051:Poliomyelitis / Q000276:immunology* / Q000473:pathology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000172:deficiency / Q000276:immunology*; D013116:Spinal Cord / Q000473:pathology; D017945:Theilovirus / Q000276:immunology*
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; D007155:Immunologic Factors; C494192:Ly-6C antigen, mouse; D004002:Clodronic Acid; D017493:Leukocyte Common Antigens; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse