The Role of Endogenous IFN-β in the Regulation of Th17 Responses in Patients with Relapsing-Remitting Multiple Sclerosis

Abstract

IFN-β has been used as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). Because only a few studies have addressed the role of endogenous IFN-β in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In vitro studies have demonstrated that IFN-β inhibits IL-17A, IL-17F, IL-21, IL-22, and IFN-γ secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion 1 and suppressor of cytokine secretion 3. We found that patients with RRMS have increased serum and cerebrospinal fluid Th17 (IL-17A and IL-17F) cytokine levels in comparison with the control subjects, suggesting that deficient endogenous IFN-β secretion or signaling can contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFN-β from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison with healthy controls. In addition, in vitro studies have revealed deficient endogenous and exogenous IFN-β signaling in the CD4+ cells derived from patients with MS. Interestingly, upon inhibition of the endogenous IFN-β signaling by silencing IFN regulatory factor (IRF) 7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22, and IL-9, suggesting that endogenous IFN-β suppresses the secretion of these pathogenic cytokines. In vivo recombinant IFN-β–1a treatment induced IFNAR1 and its downstream signaling molecules’ gene expression, suggesting that treatment reconstitutes a deficient endogenous IFN-β regulation of the CD4+ T cells’ pathogenic cytokine production in patients with MS.

Th17 cells in autoimmune diseases

“…However, determining which cell has the dominant role in the pathogenesis of MS remains a controversial topic [91,92]. Increased frequencies of circulating Th17 cells and serum IL-17A have been observed in MS [93,94]. Moreover, in vitro differentiation of myelin oligodendrocyte glycoprotein-specific Th17 cells could induce EAE.…”

IFN-β differentially regulates the function of T cell subsets in MS and EAE

“…Thorough investigation of the molecular mechanisms that underlie the beneficial effects of type I IFNs on each T cell subtype would be crucial for understanding the possibility of designing novel customized IFN-β-based therapies that selectively target and manipulate specific T cell subpopulation, thus possibly improving existing therapeutic interventions in MS. Expression of Th1 chemokines and their receptors on CD4 + T in the CNS [54] IFN-γ production by Th1 cells [53] ↓ ↓ ↑ Expression of T-bet and IFN-γ genes in the blood [43] CCR5 mRNA levels and its ligands on T cells [56] CCR5, IL-12Rβ2 and IFN-γ mRNA levels in PBMCs [57] Th17 ↓ ↓ ↓ IL-17 production by MOG-primed splenocytes [51] Frequency of CD4 + IL-17 + LN cells on day 4 of EAE [58] Frequency of CD4 + IL-17 + and CD4 + CCR6 + splenocytes and IL-17 production on day 10 of EAE [62] ↓ ↓ ↓ ↑ ↓ IL17 production by MOG-primed LN cells [28] IL17 mRNA levels in spleen and LN cells [37,64] Frequency of CD4 + IL-17 + cells in the brain [38] Production of IL-27 by DCs [38] Expression of Th17 chemokines and their receptors on CD4 + T cells in the CNS [54] ↓ IL-17A and IL-17F production by CD4 + T cells in PBMCs [63] ↓ ↓ ↓ ↓ Th17 cells differentiation in PBMCs [61,65] IL-17 mRNA and protein levels in PBMCs [66,67] Proportion of IL-17A + and IL-17F + CD4 + T cells in PBMCs [63] Expression of IL17C and IL23R genes in PBMCs [63] Tregs ↑ ↑ ↑ IL-10 production by splenocytes [28] IL-10 mRNA levels in PLP-specific T cells and IL-10 protein in PLP-primed LN cells [40] Treg proliferation [72] ↑ IL-10 and Foxp3 mRNA levels in serum and CSF [80] ↑ ↑ ↑ ↑ ↑ Treg function and proportion in peripheral blood [73] IL-10 mRNA and protein levels in PBMCs [40,82] IL-10 production by CD4 + T cells in PBMCs [65] IL-10 + cells in PBMCs [67,…”

“…A recent study by our group, using ifnar1 Tecxl mice that express IFNAR selectively on T cells, showed that endogenous IFN-β acted directly on T cells in vivo ,reducing Th17responses in the periphery on day 10 of EAE, but this effect was reversed on day 17 [62]. In addition, silencing of irf7, a factor that mediates IFN-β production, in CD4 + T cells from MS patients, led to secretion of higher levels of IL-17A and IL-17F, suggesting that endogenous IFN-β suppressed Th17 responses [63]. Besides the role of endogenous IFN-β in EAE and MS, exogenous IFN-β decreased IL-17 production by MOG-primed LN cells in vitro [28] and lessened IL-17 mRNA levels in LN and spleen cells from EAE mice [37,64].…”

“…Recently, Kvarnström performed a longitudinal study and reported that IFN-β treatment of MS patients for one year decreased IL-17 production by PBMCs [67]. Additionally, IFN-βreduced in vitro the proportion of CD4 + IL-17A + and CD4 + IL-17F + T cells from MS patients' PBMCs, while decreased in vivo gene expression of IL-17C and IL-23R in PBMCs from IFN-βtreated MS patients [63]. Conclusively, IFN-β does indeed inhibit IL-17 production in vitro and in vivo, in animal and human studies, acting directly or indirectly on T cells.…”

Immunomodulatory therapies for relapsing-remitting multiple sclerosis: monoclonal antibodies, currently approved and in testing

“…Its MOA are still not completely elucidated, but include inhibition of inflammatory cell migration across the blood-brain barrier, modification of inflammatory cytokines (inhibition of IL-12/IFN-g/IL-17-A [14] and induction of IL-10), inhibition of MHC class II expression on antigen presenting cells, and reconstitution of deficient endogenous IFN-b secretion and signaling [15]. The results of the pivotal placebocontrolled trial compared the effect of IFN-b-1b 8 million international units (MIU) and 1.6 MIU subcutaneous (S.Q.)…”