Determination of the sequential degradation of myelin proteins by macrophages

Goes, A. van der; Boorsma, W.; Hoekstra, K.; Montagne, Lisette; Groot, C. J. A. De; Dijkstra, Christine D.

doi:10.1016/j.jneuroim.2004.12.010

Cited by 31 publications

(10 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2), we used flow cytometry to quantify the expression of MBP (Fig. 7F), which we previously showed to be substantially reduced in the spinal cords of me/me mice following TMEV inoculation (65,66,104). Consistent with previous observations (65), the spinal cords of TMEV-infected me/me mice showed significantly lower MBP contents than those of the infected wild-type littermates.…”

supporting

confidence: 81%

“…In MS, intense macrophage infiltration into active demyelinating lesions is present and both the numbers and the differentiation/activation of macrophages correlate with disease severity (16,17,61,102,104). Macrophages can mediate myelin degradation, oligodendrogliopathy, and axonal loss through both cell-mediated processes and the secretion of inflammatory mediators (44,76,104).…”

Section: Discussionmentioning

confidence: 99%

“…Macrophages can mediate myelin degradation, oligodendrogliopathy, and axonal loss through both cell-mediated processes and the secretion of inflammatory mediators (44,76,104). A key area of interest is the stimulus responsible for macrophage trafficking/infiltration into CNS demyelinating lesions.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

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: 81%

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…In multiple sclerosis and animal models for MS, intense macrophage infiltration is present in active demyelinating lesions and both their numbers and differentiation/activation correlates with disease severity. 2,4,5,89,90 Macrophages can mediate myelin phagocytosis, degradation, oligodendrogliopathy, and axonal loss both through cell-mediated processes and the secretion of inflammatory mediators. 1,7,90,91 Based on our recent report of increase demyelinating activity of macrophages in me/me mice, 9 a key question was whether macrophages of MS patients display similar defects in modulation of proinflammatory cytokine signaling that may contribute to activated inflammatory profile and demyelinating activity.…”

Section: Discussionmentioning

confidence: 99%

Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype

Christophi

Panos

Hudson

et al. 2009

Laboratory Investigation

View full text Add to dashboard Cite

Recent studies in mice have demonstrated that the protein tyrosine phosphatase SHP-1 is a crucial negative regulator of pro-inflammatory cytokine signaling, TLR signaling, and inflammatory gene expression. Furthermore, mice genetically lacking SHP-1 (me/me) display a profound susceptibility to inflammatory CNS demyelination relative to wild type mice. In particular, SHP-1 deficiency may act predominantly in inflammatory macrophages to increase CNS demyelination as SHP-1-deficient macrophages display co-expression of inflammatory effector molecules and increased demyelinating activity in me/me mice. Recently, we reported that PBMCs of multiple sclerosis (MS) patients have a deficiency in SHP-1 expression relative to normal control subjects indicating that SHP-1 deficiency may play a similar role in MS as to that seen in mice. Therefore, it became essential to examine the specific expression and function of SHP-1 in macrophages from MS patients. Herein, we document that macrophages of MS patients have deficient SHP-1 protein and mRNA expression relative to those of normal control subjects. To examine functional consequences of the lower SHP-1, the activation of STAT6, STAT1, and NF-κB was quantified and macrophages of MS patients showed increased activation of these transcription factors. In accordance with this observation, several STAT6-, STAT1-, and NF-κB-responsive genes that mediate inflammatory demyelination were increased in macrophages of MS patients following cytokine and TLR agonist stimulation. Supporting a direct role of SHP-1 deficiency in altered macrophage function, experimental depletion of SHP-1 in normal subject macrophages resulted in an increased STAT/NF-κB activation and increased inflammatory gene expression to levels seen in macrophages of MS patients. In conclusion, macrophages of MS patients display a deficiency of SHP-1 expression, heightened activation of STAT6, STAT1, and NF-κB and a corresponding inflammatory profile that may be important in controlling macrophage-mediated demyelination in MS.

show abstract

“…Macrophages are the major effector cells mediating immune responses in experimental autoimmune encephalomyelitis (EAE) (Bhasin et al, 2008; Sinha et al, 2008; Youssef et al, 2002) and they determine the sequential degradation of myelin (van der Goes et al, 2005). Macrophages infiltrate the blood-brain baeeier at an early stage of EAE and initiate an inflammatory response against myelin antigens; they also act as APCs, thereby activating an antigen-specific T cell response in the CNS (Kato et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Intravenous tolerance modulates macrophage classical activation and antigen presentation in experimental autoimmune encephalomyelitis

Li¹,

Ćirić²,

Yang³

et al. 2009

Journal of Neuroimmunology

View full text Add to dashboard Cite

Macrophages act as the first line of self defense by mounting an inflammatory response to antigen and as antigen presenting cells to initiate the adaptive immune response. Inhibition of macrophage activation is one of the possible approaches to modulate inflammation. Intravenous (i.v.) tolerance has proved to be an effective method for ameliorating experimental autoimmune diseases. Whether macrophages are involved in tolerance induction is still largely undefined. In the present study we found that i.v. tolerance induction resulted in lower B7.1, B7.2 and MHC class II molecules, and reduced phagocytosis by both peritoneal macrophages and adherent splenocytes. Macrophages from tolerized mice were associated with a significantly impaired response of MOG-sensitized T cells to MOG. Macrophages from tolerized mice produced low levels of pro-inflammatory molecules IL-12, TNF-α, IL-1β, RANTES and MCP-1 and high levels of IL-10 and TGF-β. Administration of anti-TGF-β led to a reduction of IL-10 in tolerized mice. Thus, i.v. tolerance inhibits macrophage classical activation and APC function, increases macrophage alternative activation and IL-10 and TGF-β production. These cytokines, in turn, induce enhanced production of IL-10 in macrophages in MOG i.v. mice.

show abstract

Determination of the sequential degradation of myelin proteins by macrophages

Cited by 31 publications

References 18 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

Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype

Intravenous tolerance modulates macrophage classical activation and antigen presentation in experimental autoimmune encephalomyelitis

Contact Info

Product

Resources

About