Multiple Sclerosis: Modulation of Toll-Like Receptor (TLR) Expression by Interferon-β Includes Upregulation of TLR7 in Plasmacytoid Dendritic Cells

Abstract

Interferon-β is an established treatment for patients with multiple sclerosis (MS) but its mechanisms of action are not well understood. Viral infections are a known trigger of MS relapses. Toll-like receptors (TLRs) are key components of the innate immune system, which sense conserved structures of viruses and other pathogens. Effects of interferon-β on mRNA levels of all known human TLRs (TLR1-10) and the TLR adaptor molecule MyD88 were analyzed in peripheral blood mononuclear cells (PBMCs) of healthy donors by quantitative real-time PCR and by transcriptome analysis in PBMCs of 25 interferon-β-treated patients with relapsing-remitting MS. Regulation of TLR protein expression by interferon-β was investigated by flow cytometry of leukocyte subsets of healthy subjects and of untreated, interferon-β-, or glatiramer acetate-treated patients with MS. Interferon-β specifically upregulated mRNA expression of TLR3, TLR7, and MyD88 and downregulated TLR9 mRNA in PBMCs of healthy donors as well as in PBMCs of patients with MS. Plasmacytoid dendritic cells (pDCs) were identified as the major cell type responding to interferon-β with increased expression of TLR7 and MyD88 protein. In line with this, expression of TLR7 protein was increased in pDCs of interferon-β-treated, but not untreated or glatiramer acetate-treated patients with MS. Interferon-β-induced upregulation of TLR7 in pDCs is of functional relevance since pre-treatment of PBMCs with interferon-β resulted in a strongly increased production of interferon-α upon stimulation with the TLR7 agonist loxoribine. Flow cytometry confirmed pDCs as the cellular source of interferon-α production induced by activation of TLR7. Thus, upregulation of TLR7 in pDCs and a consequently increased activation of pDCs by TLR7 ligands represents a novel immunoregulatory mechanism of interferon-β. We hypothesize that this mechanism could contribute to a reduction of virus-triggered relapses in patients with MS.

Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren’s Syndrome

“…In multiple sclerosis, the role of IFN-β in the activation of TLR7 in pDCs was demonstrated [91]. In PBMCs obtained from patients with multiple sclerosis, IFN-β upregulated the mRNA of MyD88, TLR3, and TLR7, whereas TLR9 mRNA expression was suppressed.…”

RNA sensing by conventional dendritic cells is central to the development of lupus nephritis

“…Previous studies have shown that TLR7, -8, and -9 expression may be modulated by type-I IFN, which is a central mediator in the host response to viruses and has been associated with the development of clinical SLE (44)(45)(46). Therefore, the purified DC subsets were exposed to IFN-α, heat inactivated (HI) influenza virus (Flu), or active PR8-Flu.…”

Immunomodulatory activity of interferon‐beta

“…However, they downregulate TLR9, which decreases TLR9-mediated secretion of Th1-promoting interferon-alpha from the plasmacytoid dendritic cells 17. In addition, on plasmacytoid dendritic cells, interferon-beta upregulates the expression of TLR3, TLR7, and MyD88, the TLR adaptor molecule that is hypothesized to increase immune regulation and decrease the likelihood of virus-mediated MS relapses (as well as other anti-inflammatory effects that have not yet been fully explained) 21. In another mechanism, increased CCR7 expression with interferon-beta may also facilitate the channeling of T cells away from the CNS and toward peripheral lymph nodes 22.…”