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Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
2017 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

In this thesis, we have studied the immunological processes of joint inflammation that may be targets for future treatment of patients with arthritis. We focus on the immune-modulating properties of interferon-α (IFN-α) and uridine in experimental arthritis. The nucleoside uridine, which is regarded a safe treatment has anti-inflammatory properties notably by inhibiting tumor necrosis factor (TNF) release. Because the inflamed synovium in rheumatoid arthritis (RA) is characterised by pathogenic TNF-production, uridine could potentially be away to ameliorate arthritis. Systemic administration of uridine had no effect on antigeninduced arthritis (AIA), which is a T-cell dependent model where animals are immunized twice (sensitization) with bovine serum albumin (mBSA), before local triggering of arthritis by intra-articular antigen (mBSA) re-challenge. In contrast, intra-articular administration of uridine clearly down modulated development of AIA in a dose dependent manner and inhibited the expression of synovial adhesion molecules, influx of inflammatory leukocytes and synovial expression of TNF and interleukin 6, but did not affect systemic levels of proinflammatory cytokines or antigen-specific T-cell responses. Local administration of uridine may thus be a viable therapeutic option for treatment of arthritis in the future.

Viral double-stranded deoxyribonucleic acid (dsRNA), a common nucleic acid found in most viruses, can be found in the joints of RA patients and local deposition of such viral dsRNA induces arthritis by activating IFN-α. Here we show that arthritis induced by dsRNA can be mediated by IFN-producing dendritic cells in the joint and this may thus explain why viral infections are sometimes associated with arthritis.

Earlier, to study the effect of dsRNA and IFN-α in an arthritis model, that like RA, is dependent on adaptive immunity, dsRNA and IFN-α were administered individually during the development of AIA. Both molecules clearly protected against AIA in a type I IFN receptor-dependent manner but were only effective if administered in the sensitization phase of AIA. Here we show that the anti-inflammatory effect of IFN-α is critically dependent on signalling via transforming growth factor β (TGF-β) and the enzymatic activity of indoleamine 2,3 dioxygenase 1 (IDO). The IDO enzyme is produced by plasmacytoid DC and this cell type was critically required both during antigen sensitization and in the arthritis phase of AIA for the protective effect of IFN-α against AIA. In contrast, TGF-β and the enzymatic activity of IDO were only required during sensitization, which indicate that they are involved in initial steps of tolerogenic antigen sensitization. In this scenario, IFN- α first activates the enzymatic activity of IDO in pDC, which converts Tryptophan to Kynurenine, which thereafter activates TGF-β. Common for IDO-expressing pDC, Kyn and TGF-β is their ability to induce development of regulatory T cells (Tregs). We found that Tregs were crucial for IFN-α-mediated protection against AIA, but only in the arthritis phase. In line with this, adoptive transfer of Tregs isolated from IFN-α treated mice to recipient animals in the arthritis phase clearly protected against AIA. The numbers of Tregs were not significantly altered by IFN-α but IFN-α increased the suppressive capacity of Tregs against antigen-induced proliferation. This enhanced suppressive activity of Tregs in the arthritis phase was dependent on the earlier activated enzyme IDO1 during the sensitization phase of AIA. Thus, presence of IFN-α at the time of antigen sensitization activates the enzymatic activity of IDO, which generates Tregs with enhanced suppressive capacity that upon antigen re-challenge prevents inflammation. We have thus identified one example of how immune tolerance can be developed, that may be a future way to combat autoimmunity.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2017. , s. 75
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1572
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-136238DOI: 10.3384/diss.diva-136238ISBN: 9789176855416 (tryckt)OAI: oai:DiVA.org:liu-136238DiVA, id: diva2:1086176
Disputas
2017-05-04, Belladonna, Hus 511, Campus US, Linköping, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2017-03-31 Laget: 2017-03-31 Sist oppdatert: 2019-10-28bibliografisk kontrollert
Delarbeid
1. Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis
Åpne denne publikasjonen i ny fane eller vindu >>Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis
2015 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 10, s. e0141863-Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Objective Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis. Methods Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice preimmunized with mBSA. Uridine was either administered locally by direct injection into the knee joint or systemically. Systemic treatment included repeated injections or implantation of a pellet continuously releasing uridine during the entire experimental procedure. Anti-mBSA specific immune responses were determined by ELISA and cell proliferation and serum cytokine levels were determined by Luminex. Immunohistochemistry was used to identify cells, study expression of cytokines and adhesion molecules in the joint. Results Local administration of 25-100 mg/kg uridine at the time of arthritis onset clearly prevented development of joint inflammation. In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis. Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis. In contrast, local uridine treatment efficiently inhibited synovial expression of ICAM-1 and CD18, local cytokine production and recruitment of leukocytes to the synovium. Conclusion Local, but not systemic administration of uridine efficiently prevented development of antigen- induced arthritis. The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation. Further, uridine is a small, inexpensive molecule and may thus be a new therapeutic option to treat joint inflammation in RA.

sted, utgiver, år, opplag, sider
PUBLIC LIBRARY SCIENCE, 2015
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-123070 (URN)10.1371/journal.pone.0141863 (DOI)000363920300089 ()26512984 (PubMedID)
Merknad

Funding Agencies|Vetenskapsradet-Grant [521-2011-3095]; Reumatikerforbundet Grant [155261]; County Council of Ostergotland, Sweden; Linkoping University

Tilgjengelig fra: 2015-12-04 Laget: 2015-12-03 Sist oppdatert: 2017-12-01
2. IDO1 and TGF-beta Mediate Protective Effects of IFN-alpha in Antigen-Induced Arthritis
Åpne denne publikasjonen i ny fane eller vindu >>IDO1 and TGF-beta Mediate Protective Effects of IFN-alpha in Antigen-Induced Arthritis
Vise andre…
2016 (engelsk)Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 197, nr 8, s. 3142-3151Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

IFN-alpha prevents Ag-induced arthritis (AIA), and in this study we investigated the role of IDO1 and TGF-beta signaling for this anti-inflammatory property of IFN-alpha. Arthritis was induced by methylated BSA (mBSA) in mBSA-sensitized wild-type (WT), Ido1(-/-), or Ifnar(-/-) mice, treated or not with IFN-alpha or the IDO1 product kynurenine (Kyn). Enzymatic IDO1 activity, TGF-beta, and plasmacytoid dendritic cells (pDC) were neutralized by 1-methyltryptophan and Abs against TGF-beta and pDC, respectively. IDO1 expression was determined by RT-PCR, Western blot, and FACS, and enzymatic activity by HPLC. Proliferation was measured by H-3-thymidine incorporation and TGF-beta by RT-PCR and ELISA. WT but not Ido1(-/-) mice were protected from AIA by IFN-alpha, and Kyn, the main IDO1 product, also prevented AIA, both in WTand Ifnar(-/-) mice. Protective treatment with IFN-alpha increased the expression of IDO1 in pDC during AIA, and Ab-mediated depletion of pDC, either during mBSA sensitization or after triggering of arthritis, completely abrogated the protective effect of IFN-alpha. IFN-alpha treatment also increased the enzymatic IDO1 activity (Kyn/tryptophan ratio), which in turn activated production of TGF-beta. Neutralization of enzymatic IDO1 activity or TGF-beta signaling blocked the protective effect of IFN-alpha against AIA, but only during sensitization and not after triggering of arthritis. Likewise, inhibition of the IDO1 enzymatic activity in the sensitization phase, but not after triggering of arthritis, subdued the IFN-alpha-induced inhibition of mBSA-induced proliferation. In conclusion, presence of IFN-alpha at Ag sensitization activates an IDO1/TGF-beta-dependent anti-inflammatory program that upon antigenic rechallenge prevents inflammation via pDC.

sted, utgiver, år, opplag, sider
AMER ASSOC IMMUNOLOGISTS, 2016
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-133121 (URN)10.4049/jimmunol.1502125 (DOI)000387965100018 ()27647832 (PubMedID)
Tilgjengelig fra: 2016-12-12 Laget: 2016-12-09 Sist oppdatert: 2019-02-11
3. Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.
Åpne denne publikasjonen i ny fane eller vindu >>Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.
2014 (engelsk)Inngår i: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 95, nr 4, s. 661-666Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Viral dsRNA can be found at the site of inflammation in RA patients, and intra-articular injection of dsRNA induces arthritis by activating type I IFN signaling in mice. Further, DCs, a major source of IFN-α, can be found in the synovium of RA patients. We therefore determined the occurrence of DCs in dsRNA-induced arthritis and their ability to induce arthritis. Here, we show, by immunohistochemistry, that cells expressing the pan-DC marker CD11c and the pDC marker 120G8 are present in the inflamed synovium in dsRNA-induced arthritis. Flt3L-generated and splenic DCs preactivated with dsRNA before intra-articular injection, but not mock-stimulated cells, clearly induced arthritis. Induction of arthritis was dependent on type I IFN signaling in the donor DCs, whereas IFNAR expression in the recipient was not required. Sorting of the Flt3L-DC population into cDCs (CD11c(+), PDCA-1(-)) and pDCs (CD11c(+), PDCA-1(+)) revealed that both subtypes were arthritogenic and produced type I IFN if treated with dsRNA. Taken together, these results demonstrate that viral nucleic acids can elicit arthritis by activating type I IFN signaling in DCs. Once triggered, autocrine type I IFN signaling in dsRNA-activated DCs is sufficient to propagate arthritis.

sted, utgiver, år, opplag, sider
Society for Leukocyte Biology, 2014
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-102370 (URN)10.1189/jlb.0613320 (DOI)000335346300011 ()24304616 (PubMedID)
Tilgjengelig fra: 2013-12-09 Laget: 2013-12-09 Sist oppdatert: 2017-12-06

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