scholarly journals Mycophenolic Acid, Active Form of Mycophenolate Mofetil, Interferes With the IRF7 Nuclear Translocation and Type I IFN Production by Plasmacytoid Dendritic Cells

2020 ◽  
Author(s):  
Minoru Shigesaka ◽  
Tomoki Ito ◽  
Muneo Inaba ◽  
Kai Imai ◽  
Hideki Yamanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycophenolate Mofetil ◽  
Mycophenolic Acid ◽  
Lupus Erythematosus ◽  
Nuclear Translocation ◽  
Active Form ◽  
Inhibitory Effect ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Alternative Treatment Strategy

Abstract BackgroundBoth humoral and cellular immune mechanisms are involved in the onset and progression of the autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLEvia the dysregulation of type I interferon (IFN) production;these cells act together with activated myeloid DCs (mDCs), to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of the aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMFin targeting DC functions, especially the IFN response of pDCs.MethodsWe isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-a production.ResultsWe found that treatment with 1-10mM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs(but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation in pDCsand IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs.ConclusionsOur data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disordersby regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

scholarly journals Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Minoru Shigesaka ◽  
Tomoki Ito ◽  
Muneo Inaba ◽  
Kai Imai ◽  
Hideki Yamanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycophenolate Mofetil ◽  
Mycophenolic Acid ◽  
Lupus Erythematosus ◽  
Nuclear Translocation ◽  
Active Form ◽  
Autoimmune Disorders ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Alternative Treatment Strategy

Abstract Background Both humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs. Methods We isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-α production. Results We found that treatment with 1−10 μM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs. Conclusions Our data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

scholarly journals Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells

2020 ◽  
Author(s):  
Minoru Shigesaka ◽  
Tomoki Ito ◽  
Muneo Inaba ◽  
Kai Imai ◽  
Hideki Yamanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycophenolate Mofetil ◽  
Mycophenolic Acid ◽  
Lupus Erythematosus ◽  
Nuclear Translocation ◽  
Active Form ◽  
Autoimmune Disorders ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Alternative Treatment Strategy

Abstract Background Both humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs. Methods We isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-a production.Results We found that treatment with 1-10 mM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs. Conclusions Our data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

AB0141 MYCOPHENOLATE MOFETIL, INHIBITOR OF INOSINE-5’-MONOPHOSPHATE DEHYDROGENASE, REGULATES DIFFERENTIATION, MATURATION AND FUNCTION OF HUMAN DENDRITIC CELL SUBSETS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1370.1-1371
Author(s):  
M. Shigesaka ◽  
T. Ito ◽  
M. Inaba ◽  
Y. Azuma ◽  
S. Tsujimoto ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dendritic Cells ◽  
Mycophenolate Mofetil ◽  
Human Blood ◽  
Mycophenolic Acid ◽  
Lupus Erythematosus ◽  
Human Monocyte ◽  
Type I ◽  
Systemic Lupus ◽  
And Function

Background:Systemic lupus erythematosus (SLE) is a heterogeneous disease in which excessive inflammation, autoantibodies, and complement activation lead to multisystem tissue damage. Plasmacytoid dendritc cells (pDCs) play a central role in the pathogenesis of SLE through dysregulated type I IFN production, together with activated myeloid DCs (mDCs), amplifying vicious spiral of autoimmune disorders(1). Therefore, control of the aberrant DC activation may provide an alternative treatment strategy against SLE.Objectives:Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks proliferation of B and T lymphocytes by inhibition of inosine-5-monophosphate dehydrogenase (IMPDH). In addition, although there is evidence indicating the immunosuppressive effects of MMF on human monocyte-derived dendritic cells(2.3), there are no reports showing its effects on human blood DC subsets. Here we focused on the effects of MMF on the functions of the blood pDCs and mDCs.Methods:We isolated human blood DCs from healthy donors using cell sorting(4) and examined the function of mycophenolic acid (MPA), which is metabolic products of MMF, on DC subsets in response to TLR-ligands and serum from patients with active SLE. Written informed consent was obtained from all healthy adult donors and SLE patients.Results:We found that therapeutic plasma concentration range of MPA down-regulated expression of CD40, CD80 and CD86 dose-dependently on mDCs and pDCs without inducing apoptosis, in response to R848(TLR7/8 agonist) and CpG2216(TLR9 agonist), respectively. Of note, MPA profoundly suppressed IL-12 production and STAT4 expression in the mDCs and IFN-α production and IRF7 expression in the pDCs(Fig 1). We also obserbed inhibition of nuclear translocation of IRF-7 in pDCs treated with MPA by confocal microscopy(Fig 2). Furthermore,we identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by human PBMCs.Conclusion:Our data suggest that MMF can drive a wedge into the vicious spiral of autoimmune disorders through regulating the function of not only lymphocyte but also DC subsets. Thus, we unveiled a part mechanism of the therapeutic ability of MMF against SLE.References:[1]A Plasmacytoid Dendritic Cells-Type I Interferon Axis is Critically Implicated in the Pathogenesis of Systemic Lupus Erythematosus. Int. J. Mol. Sci. 2015: 16, 14158-14170.[2]Mycophenolate mofetil inhibits differentiation, maturation and allostimulatory function of human monocyte-derived dendritic cells. Clin Exp Immunol. 2003;134:63-69.[3]Mycophenolic acid inhibits maturation and function of human dendritic cells and B cells. Human Immunol. 2009;70: 692–700.[4]Miyamoto et al. Arthritis Research & Therapy 2010, 12:R87.Disclosure of Interests:None declared

U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3229-3234 ◽  
Author(s):  
Emina Savarese ◽  
Ohk-wha Chae ◽  
Simon Trowitzsch ◽  
Gert Weber ◽  
Berthold Kastner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Immune Complexes ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Dependent Manner ◽  
Stem Loop ◽  
Murine Bone Marrow ◽  
Small Nuclear Ribonucleoprotein ◽  
Nuclear Antigens

Abstract Plasmacytoid dendritic cells (PDCs), which produce IFN-α in response to autoimmune complexes containing nuclear antigens, are thought to be critically involved in the pathogenesis of systemic lupus erythematosus (SLE). One of the immunostimulatory components of SLE immune complexes (SLE-ICs) is self DNA, which is recognized through Tlr9 in PDCs and B cells. Small nuclear ribonucleoproteins (snRNPs) are another major component of SLE-ICs in 30% to 40% of patients. In this study, we show that murine PDCs are activated by purified U1snRNP/anti-Sm ICs to produce IFN-α and proinflammatory cytokines and to up-regulate costimulatory molecules. The induction of IFN-α and IL-6 by U1snRNPs in murine bone marrow–derived PDCs required the presence of intact U1RNA and was largely dependent on Tlr7 but independent of Tlr3. Intracellularly delivered isolated U1snRNA and oligoribonucleotides derived from the stem loop regions and the Sm-binding site of U1snRNA efficiently induced IFN-α and IL-6 in Flt3L-cultured DCs in a Tlr7-dependent manner. The U1snRNA component of U1snRNP immune complexes, found in patients with SLE, acts as an endogenous “self” ligand for Tlr7 and triggers IFN-α and IL-6 production in PDCs.

scholarly journals Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Antonios Psarras ◽  
Adewonuola Alase ◽  
Agne Antanaviciute ◽  
Ian M. Carr ◽  
Md Yuzaiful Md Yusof ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Type I Interferon ◽  
Connective Tissue Diseases ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Interferon Production ◽  
Interferon Signature

AbstractAutoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity.

scholarly journals Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus

2014 ◽  
Vol 211 (10) ◽  
pp. 1969-1976 ◽  
Author(s):  
Vanja Sisirak ◽  
Dipyaman Ganguly ◽  
Kanako L. Lewis ◽  
Coline Couillault ◽  
Lena Tanaka ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Gene Dosage ◽  
Gene Expression Signature ◽  
Plasmacytoid Dendritic Cells ◽  
Genetic Evidence ◽  
Type I ◽  
Systemic Lupus ◽  
Autoantibody Production

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of antibodies to self-nucleic acids, immune complex deposition, and tissue inflammation such as glomerulonephritis. Innate recognition of self-DNA and -RNA and the ensuing production of cytokines such as type I interferons (IFNs) contribute to SLE development. Plasmacytoid dendritic cells (pDCs) have been proposed as a source of pathogenic IFN in SLE; however, their net contribution to the disease remains unclear. We addressed this question by reducing gene dosage of the pDC-specific transcription factor E2-2 (Tcf4), which causes a specific impairment of pDC function in otherwise normal animals. We report that global or DC-specific Tcf4 haplodeficiency ameliorated SLE-like disease caused by the overexpression of the endosomal RNA sensor Tlr7. Furthermore, Tcf4 haplodeficiency in the B6.Sle1.Sle3 multigenic model of SLE nearly abolished key disease manifestations including anti-DNA antibody production and glomerulonephritis. Tcf4-haplodeficient SLE-prone animals showed a reduction of the spontaneous germinal center reaction and its associated gene expression signature. These results provide genetic evidence that pDCs are critically involved in SLE pathogenesis and autoantibody production, confirming their potential utility as therapeutic targets in the disease.

scholarly journals Plasmacytoid dendritic cells are functionally exhausted while non-haematopoietic sources of type I interferon dominate human autoimmunity

2018 ◽  
Author(s):  
Antonios Psarras ◽  
Adewonuola Alase ◽  
Agne Antanaviciute ◽  
Ian M. Carr ◽  
Md Yuzaiful Md Yusof ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Connective Tissue Diseases ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Type I ◽  
Effector Cells ◽  
Transcriptional Signature

ABSTRACTAutoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons (IFNs) have a crucial role in the progression to established autoimmune diseases such as systemic lupus erythematosus (SLE). However, their cellular source and regulation in disease initiation are unclear. The current paradigm suggests that plasmacytoid dendritic cells (pDCs) are activated in SLE contributing to excessive IFN production. Here, we show that in preclinical autoimmunity, established SLE, and primary Sjögren’s Syndrome, pDCs are not effector cells, but rather have lost their capacity for TLR-mediated IFN-α and TNF production and fail to induce T cell activation, independently of disease activity and blood IFN signature. In addition, pDCs present a transcriptional signature of cellular stress and senescence accompanied by increased telomere erosion. Instead, we demonstrate a marked enrichment of IFN signature in non-lesional skin in preclinical autoimmunity. In these individuals and SLE patients, type I IFNs were abundantly produced by keratinocytes in the absence of infiltrating leucocytes. These findings revise our understanding of the role of IFN in the initiation of human autoimmunity, with non-haematopoietic tissues perpetuating IFN responses, which in turn predict clinical disease. These data indicate potential therapeutic targets outside the conventional immune system for treatment and prevention.

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