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 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.

CD300F Blocks Both MyD88 and TRIF-Mediated TLR Signaling through Activation of Src Homology Region 2 Domain-Containing Phosphatase 1

“…In lymphocytes and myeloid cells, SHP-1 has been demonstrated to modulate cellular signals that involve PI3K, Janus kinase 2, STATs, MAPKs, ERK, and NF-kB (35,36). As a result, SHP-1 deficiency resulted in enhanced macrophage activities in clinical cases and experimental models (37)(38)(39). Phosphorylation of CD300F and its subsequent interaction with SHP-1 lead to the phosphorylation and activation of SHP-1.…”

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

“…It remains possible that single or multiple cell subsets express increased levels of the enzymes. Both decreases14 and increases20 in ARG1 in monocytes from MS patients have been previously reported.…”

“…In the Argentinian study, culture of the blood cells also altered IDO1 and ARG1 expression. Increased ARG1 expression in PBMCs from MS patients is supported by a study of macrophages from the blood of disease‐modifying treatment (DMT)‐free patients with established MS 20. These cells expressed increased ARG1 in vitro, and they were more susceptible to activation with an enhanced ability, relative to macrophages from normal people, to skew towards inducible NOS‐ or ARG‐expressing cells in the presence of LPS or IL‐4, respectively 20…”

Gene Expression Changes in Multiple Sclerosis Relapse Suggest Activation of T and Non-T Cells

“…Where their function is known, many of the decreased transcripts have a regulatory or inhibitory role. CDKN1C and ZAK are both likely inhibitors of cell division, IL1RN inhibits the activity of interleukin-1, and PILRA has a tyrosine-based inhibitory motif and regulates the protein tyrosine phosphatase SHP-1, which is central in the control of cell signaling and may be altered in MS (12). The downregulation of mRNA for inhibitory proteins suggests that the non-T cells are becoming activated.…”

“…Dendrogram constructed using BRB ArrayTools with centered correlation and average linkage. The branch labels give the experiment number (1)(2)(3)(4)(5), the subject number (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), clinical status, treatment, and gender. The samples from the first two experiments formed large clusters.…”