title: Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype.
abstract: 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-kappaB was quantified and macrophages of MS patients showed increased activation of these transcription factors. In accordance with this observation, several STAT6-, STAT1-, and NF-kappaB-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-kappaB 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-kappaB and a corresponding inflammatory profile that may be important in controlling macrophage-mediated demyelination in MS.
authors.affiliation: Department of Neurology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: George P
authors.initials: GP
authors.lastname: Christophi
authors.forename: Michael
authors.initials: M
authors.lastname: Panos
authors.forename: Chad A
authors.initials: CA
authors.lastname: Hudson
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Christophi
authors.forename: Ross C
authors.initials: RC
authors.lastname: Gruber
authors.forename: Akos T
authors.initials: AT
authors.lastname: Mersich
authors.forename: Scott D
authors.initials: SD
authors.lastname: Blystone
authors.forename: Burk
authors.initials: B
authors.lastname: Jubelt
authors.forename: Paul T
authors.initials: PT
authors.lastname: Massa
mesh_terms: D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D003711:Demyelinating Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008264:Macrophages / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000172:deficiency* / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism
chemical_list: D016207:Cytokines; D017931:DNA Primers; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6