Critical Role for Protein Tyrosine Phosphatase SHP-1 in Controlling Infection of Central Nervous System Glia and Demyelination by Theiler's Murine Encephalomyelitis Virus

Massa, Paul T.; Ropka, Stacie L.; Saha, Sucharita; Fecenko, Karen L.; Beuler, Kathryn L.

doi:10.1128/jvi.76.16.8335-8346.2002

Cited by 18 publications

(37 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mice genetically lacking SHP-1 (motheaten mice) display myelin deficiency, which may be mediated by increased innate inflammatory mediators in the CNS (66,69). Furthermore, motheaten mice are highly susceptible to experimentally induced demyelinating disease (30,65). Taken together, the findings of these studies indicate that SHP-1 is a key regulator of inflammation in the CNS that may be relevant to the pathogenesis of MS.…”

supporting

confidence: 53%

“…Previously, we have shown that SHP-1-deficient mice uniquely display unusually rapid CNS demyelination associated with extensive white-matter cellular infiltration and clinical paralysis within the first week of TMEV infection compared to their wild-type littermates (65). These data suggested that SHP-1 modulates early events in TMEV infections of the CNS which cause inflammatory demyelination.…”

mentioning

confidence: 84%

See 1 more Smart Citation

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

Christophi

Hudson

Panos³

et al. 2009

J Virol

Self Cite

View full text Add to dashboard Cite

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 Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that remains a major cause of disability (76). Several studies demonstrated that MS lesions contain multiple leukocyte cell types, including lymphocytes, macrophages, and dendritic cells, all of which are believed to contribute to lesion formation by various distinct and interacting mechanisms (54, 61). Among these leukocyte subsets, infiltrating macrophages have been identified as major effectors of demyelination in both MS and animal models for MS (17,44,59,102). In accord with these studies, it was recently reported that the dominant mechanism of demyelination in MS is macrophage mediated (15). Indeed, in some models for MS, the requirement for lymphocytes is negligible and macrophages are the sole mediators of demyelination (6, 72).These findings have stimulated intense interest in the function of macrophages in lesion formation, including signaling events that draw these cells into the CNS white matter and trigger the effector mechanisms by which these cells damage myelin. For instance, macrophages have been identified as the major responders to CNS chemokines and producers of a number of proinflammatory cytokines, chemokines, and toxic molecules known to promote demyelination (32,44,63,85,90,91,93,103). Interestingly, both the brains of MS patients and the brains of experimental animals with MS-like diseases contain activated transcription factors like NF-B (34, 40), STAT1 (35,37,40), and STAT6 (18,21,109), which can lead to enhanced expression of these inflammatory molecules. Based on the findings of our previous work, we propose that the modulation of inflammatory signaling via these transcriptional pathways may be deficient in the leukocytes, including the macrophages, of MS patients and that this deficiency is responsible for susceptibility to inflammatory demyelinating processes within the CNS.SHP-1 is a protein tyrosine phosphatase with two Src homology 2 domains which acts as a negative regulator of both innate and acquired immune cytokine signaling via NF-B (52, 67), STAT1 (29,68), and STAT6 (13,43,45,50). Mice genetically lacking SHP-1 (motheaten mice) display myelin de...

show abstract

supporting

confidence: 53%

mentioning

confidence: 84%

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

Christophi

Hudson

Panos³

et al. 2009

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…The intermediary role of cytokines in virus-induced SHP-1 was supported by the loss of SHP-1 induction in vivo in STAT-1-and IRF-1-null mice. In agreement with previous observations that complete loss of SHP-1 leads to augmented viral loads and inflammation following TMEV infection (Massa et al 2002), an increase in SHP-1 activity would be expected to counteract viral replication partly through increased iNOS activity as recently reported by us (Bonaparte et al 2006). Moreover, the role of iNOS and NO in inhibiting NF-jB activity and tissue inflammation in tissues including the CNS has been demonstrated (Arnett et al 2002;Ckless et al 2007).…”

Section: Discussionsupporting

confidence: 74%

“…However, recent evidence indicates that chronic constitutive inflammation and especially increased production of reactive oxygen species in the CNS of SHP-1-deficient mice during the period of active myelination may be responsible for the observed effects on myelin. Additionally, when motheaten mice are infected with TMEV, me/me mice show severe inflammatory demyelination compared to +/+ littermates (Massa et al 2002). Similarly, mice deficient in SHP-1 developed a more severe course of experimental allergic encephalomyelitis and a more pronounced inflammatory profile compared to wildtype mice (Deng et al 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, it was recently shown that leukocytes of MS patients have decreased levels of the phosphatase SHP-1, which results in increased inflammatory gene expression (Christophi et al 2008). Furthermore, SHP-1 plays a critical role in fighting CNS viral infections such as Theiler's murine encephalomyelitis virus (TMEV) (Massa et al 2002). We have recently shown that SHP-1 deficiency leads to higher viral replication as a result of unrestrained STAT-6-dependent arginase I gene expression and reduced nitric oxide production in CNS glia (Massa et al 2002;Bonaparte et al 2006).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Promoter‐specific induction of the phosphatase SHP‐1 by viral infection and cytokines in CNS glia

Christophi¹,

Hudson²,

Gruber³

et al. 2008

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

We have previously shown that the protein tyrosine phosphatase SHP-1 is highly expressed in CNS glia and is an important modulator of cytokine signaling. As such, mice genetically lacking SHP-1 display constitutive myelin abnormalities, severe virus-induced demyelinating disease, and defects in innate anti-viral responses in the CNS. In this study, we show the differential distribution of the SHP-1 promoterspecific transcripts and demonstrate that several cytokines significantly induce SHP-1 expression in CNS glia. Consistent with these cytokine effects, infection with a neurotropic virus both in vitro and in vivo up-regulates SHP-1 transcripts and protein in CNS cells. Using CNS glial cultures of gene knockout mice, we show that interferons-b and interferons-c act through STAT-1 and interferon regulatory factor-1 to induce the SHP-1 promoter I transcripts. Conversely, interferons-b and IL-6 act through STAT-3 to induce SHP-1 promoter II transcripts. This study demonstrates that interferons and other cytokines associated with virus infections in the CNS can significantly induce the expression of SHP-1 through STAT-1/3 activity and provides a better understanding of the molecular mechanisms regulating cytokine-induced expression important for multiple homeostatic functions of SHP-1 in the CNS.

show abstract

Inverse regulation of inducible nitric oxide synthase (iNOS) and arginase I by the protein tyrosine phosphatase SHP-1 in CNS glia

Bonaparte

Hudson

et al. 2006

Glia

Self Cite

View full text Add to dashboard Cite

We have previously shown that the SH2 domain-containing protein tyrosine phosphatase SHP-1 plays a critical role in controlling virus infection in CNS glia in vivo and in vitro. The present study addressed whether increased virus replication in SHP-1-deficient glia in vitro may be a result of altered expression of inducible nitric oxide synthase (iNOS/NOS2). First, we observed a profound reduction in iNOS protein expression and production of nitric oxide (NO) in response to the viral mimic double-stranded RNA (dsRNA), despite the induction of high levels of iNOS mRNA, in SHP-1-deficient motheaten mouse compared to wild type littermate mouse glia. Because both iNOS expression and NO production are suppressed by multiple pathways involving arginase I activity, it was important that we observed abnormally high constitutive expression of arginase I in cultured glia of SHP-1-deficient compared to wild type mice. Further, both constitutive and IL-4/IL-10-induced expression of arginase I correlated with elevated STAT6 nuclear binding activity, decreased NO production, and increased virus replication in motheaten compared to wild type astrocytes. These findings provide the first evidence of an inverse relationship between NO and arginase I activity regulated by SHP-1 in CNS glia that is relevant to modulation of innate anti-viral responses. Thus, we propose that SHP-1 is a critical regulator of innate immunity to virus infections in CNS cells.

show abstract

Critical Role for Protein Tyrosine Phosphatase SHP-1 in Controlling Infection of Central Nervous System Glia and Demyelination by Theiler's Murine Encephalomyelitis Virus

Cited by 18 publications

References 68 publications

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

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

Promoter‐specific induction of the phosphatase SHP‐1 by viral infection and cytokines in CNS glia

Inverse regulation of inducible nitric oxide synthase (iNOS) and arginase I by the protein tyrosine phosphatase SHP-1 in CNS glia

Contact Info

Product

Resources

About