Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype
Laboratory Investigation, ISSN: 0023-6837, Vol: 89, Issue: 7, Page: 742-759
2009
- 70Citations
- 68Captures
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Metrics Details
- Citations70
- Citation Indexes70
- 70
- CrossRef68
- Captures68
- Readers68
- 68
Article Description
Recent studies in mice have demonstrated that the protein tyrosine phosphatase SHP-1 is a crucial negative regulator of proinflammatory 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 coexpression 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- κ B was quantified and macrophages of MS patients showed increased activation of these transcription factors. In accordance with this observation, several STAT6-, STAT1-, and NF- κ B-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- κ B 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- κ B and a corresponding inflammatory profile that may be important in controlling macrophage-mediated demyelination in MS.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0023683722029865; http://dx.doi.org/10.1038/labinvest.2009.32; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=67649833763&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/19398961; https://linkinghub.elsevier.com/retrieve/pii/S0023683722029865; https://dx.doi.org/10.1038/labinvest.2009.32
Elsevier BV
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