Plasmacytoid Dendritic Cells and Immunotherapy in Multiple Sclerosis

Glehn, Felipe von; Santos, Leonilda Maria Barbosa dos; Balashov, Konstantin

doi:10.2217/imt.12.117

Cited by 18 publications

(14 citation statements)

References 103 publications

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“…We further postulate that other G protein-coupled receptors may use similar mechanisms to regulate IFN-I amplification and possibly other diverse biological responses. Because pDCs are causal effectors in the pathogenesis of autoimmune disorders, including lupus and psoriasis (24), and have been linked to disease progression in animal models of multiple sclerosis and ulcerative colitis (25,26), our study indicates that the efficacy of S1PR1 therapies in these disease states may manifest through attenuation of an IFNAR1 cytokine amplification loop. The role of this pathway in therapeutic efficacy and as a biomarker for patient subsets that might benefit from S1PR1 agonist therapies warrants exploration.…”

Section: Significancementioning

confidence: 84%

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

Teijaro

Studer

Leaf

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Blunting immunopathology without abolishing host defense is the foundation for safe and effective modulation of infectious and autoimmune diseases. Sphingosine 1-phosphate receptor 1 (S1PR1) agonists are effective in treating infectious and multiple autoimmune pathologies; however, mechanisms underlying their clinical efficacy are yet to be fully elucidated. Here, we uncover an unexpected mechanism of convergence between S1PR1 and interferon alpha receptor 1 (IFNAR1) signaling pathways. Activation of S1PR1 signaling by pharmacological tools or endogenous ligand sphingosine-1 phosphate (S1P) inhibits type 1 IFN responses that exacerbate numerous pathogenic conditions. Mechanistically, S1PR1 selectively suppresses the type I IFN autoamplification loop in plasmacytoid dendritic cells (pDCs), a specialized DC subset, for robust type I IFN release. S1PR1 agonist suppression is pertussis toxin-resistant, but inhibited by an S1PR1 C-terminal-derived transactivating transcriptional activator (Tat)-fusion peptide that blocks receptor internalization. S1PR1 agonist treatment accelerates turnover of IFNAR1, suppresses signal transducer and activator of transcription 1 (STAT1) phosphorylation, and downmodulates total STAT1 levels, thereby inactivating the autoamplification loop. Inhibition of S1P-S1PR1 signaling in vivo using the selective antagonist Ex26 significantly elevates IFN-α production in response to CpG-A. Thus, multiple lines of evidence demonstrate that S1PR1 signaling sets the sensitivity of pDC amplification of IFN responses, thereby blunting pathogenic immune responses. These data illustrate a lipid G-protein coupled receptor (GPCR)-IFNAR1 regulatory loop that balances effective and detrimental immune responses and elevated endogenous S1PR1 signaling. This mechanism will likely be advantageous in individuals subject to a range of inflammatory conditions. sphingosine 1-phosphate | S1PR1 | plasmacytoid dendritic cell | interferon-α | IFNAR1

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Section: Significancementioning

confidence: 84%

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

Teijaro

Studer

Leaf

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…pDCs have been identified in the CNS of mice with EAE as well as in the cerebrospinal fluid of MS patients suggesting their active participation in the immunopathogenesis of neuroinflammation . Indeed in mice with EAE, active depletion of pDCs was found to aggravate disease symptoms suggesting a protective role of pDCs once recruited into the inflamed CNS.…”

Section: Discussionmentioning

confidence: 99%

CD49d/CD29‐integrin controls the accumulation of plasmacytoid dendritic cells into the CNS during neuroinflammation

et al. 2019

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Plasmacytoid dendritic cells (pDCs) are found in the CNS during neuroinflammation andhave been reported to exert regulatory functions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). However, the mechanisms of entry of pDCs into the CNS as well as their phenotype and innate functional properties, once recruited into the CNS, have not been thoroughly examined. Herein, we show that pDCs rapidly accumulate into the brain and spinal cord during the acute phase of EAE, and maintain the expression of numerous phenotypic markers typical of peripheral pDCs. Functionally, CNS-pDCs constitutively expressed IRF7 and were able to rapidly produce type I IFNs and IL-12p40 upon ex vivo TLR-9 stimulation. Using adoptive transfer experiments, we provide evidence that CNS-pDC are recruited from the blood and accumulate into the CNS during the acute phase of EAE. Accumulation of pDCs into the CNS was strongly inhibited in the absence of CD29, but not CD18, suggesting a major role for ß1 but not ß2 integrins. Indeed, blocking the CD49d α4-integrins during acute EAE drastically diminished CNS-pDC numbers. Together, our results demonstrate that circulating pDCs are actively recruited into the CNS during acute EAE through a mechanism largely dependent on CD49d/CD29-integrins.Keywords: CD29 integrins r cell trafficking r CNS autoimmunity r innate immunity r plasmacytoid dendritic cells Additional supporting information may be found online in the Supporting

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“…However, pDCs seem to exert ambivalent functions in this disease, as also assessed by the contrasting results obtained in EAE (reviewed in Ref. [210]). One study described that pDCs depletion by anti-BST2 antibodies prior to induction of the disease decreases its severity, showing a reduced role for type I IFNs in this phenotype, which instead depended on pDC-dependent priming of autoimmune Th17 CD4 þ lymphocytes [211].…”

Section: Pdc-derived Type I Ifns In Autoimmunitymentioning

confidence: 97%