Systemic Macrophage Activation in Locally-induced Experimental Arthritis

Simon, J.; Surber, Ralf; Kleinstäuber, Gesa; Petrow, Peter; Henzgen, S.; Kinne, Raimund W.; Bräuer, Rolf

doi:10.1006/jaut.2001.0534

Cited by 45 publications

(52 citation statements)

References 48 publications

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“…28 and 29). In murine AIA, temporal changes in TNF␣, IL-1␤, and IFN␥ expression occur during the acute phase, 1 day after arthritis induction (30,31). We observed that levels of TNF␣ and IL-1␤ expression in synovial tissues were not significantly different between IFN␥ Ϫ/Ϫ and IFN␥ ϩ/ϩ mice at this time; furthermore, titers of antibody to mBSA were comparable (data not shown).…”

Section: Discussionmentioning

confidence: 71%

Interferon‐γ protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints

Williams

Richards

Thomas

et al. 2007

Arthritis & Rheumatism

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Objective. Local interaction between soluble mediators within the inflamed synovium is a key factor that governs the pathologic outcome of inflammatory arthritides. Our aim was to investigate the interplay between the Th1 lymphokine interferon-␥ (IFN␥) and pivotal cytokines that drive rheumatoid arthritis ( ) mice. Joint swelling was measured and histologic analysis was performed in order to assess changes in both inflammatory and degenerative parameters in vivo. In vitro, the influence of IFN␥ in regulating IL-1␤-and TNF␣-driven CXCL8 and CCL2 production was quantified by enzyme-linked immunosorbent assay.Results. In murine AIA, both inflammatory and degenerative arthritis parameters were significantly exacerbated in the absence of IFN␥. IFN␥ appeared to be a crucial factor in regulating CXCR2؉ neutrophil influx in the joint. In in vitro studies using RA fibroblastlike synoviocytes, IFN␥ modulated both IL-1␤-and TNF␣-driven chemokine synthesis, resulting in the down-regulation of CXCL8 production.Conclusion. IFN␥ exerts antiinflammatory, chondroprotective, and antiosteoclastogenic effects in murine AIA through a mechanism that involves the regulation of chemokine synthesis and local neutrophil recruitment. These studies suggest a potential therapeutic role of modulating IFN␥ signaling in the treatment of inflammatory arthritides.

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Section: Discussionmentioning

confidence: 71%

Interferon‐γ protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints

Williams

Richards

Thomas

et al. 2007

Arthritis & Rheumatism

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show abstract

“…For histopathological examination, knee joints were removed, fixed in toto in 4.5% formalin, decalcified in EDTA, and embedded in paraffin. Sections were stained with H&E. The specimens were evaluated in a blinded manner according to a macroscopic scoring system ranging from 0 to 3, with consideration of acute and chronic inflammation in the synovial and periarticular tissues, as well as destruction of cartilage and bone as described (22). Acute inflammation reflects exudation and infiltration of granulocytes, whereas chronic inflammation denoted synovial hyperplasia, infiltration of mononuclear cells, and fibrosis.…”

Section: Clinical Assessment Of Aiamentioning

confidence: 99%

Exacerbation of Antigen-Induced Arthritis in IFN-γ-Deficient Mice As a Result of Unrestricted IL-17 Response

Irmler

Gajda

Bräuer

2007

The Journal of Immunology

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121

103

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Proinflammatory Th1 responses are believed to be involved in the induction and perpetuation of rheumatoid arthritis. However, the role of IFN-γ, the major cytokine produced by Th1 cells, is still incompletely defined. In the present study, we investigated the effects of IFN-γ deficiency (IFN-γ−/−) on the course of experimental murine Ag-induced arthritis (AIA). In the acute stage of disease, IFN-γ−/− AIA mice showed significantly increased inflammatory responses compared with wild-type C57BL/6 AIA mice, i.e., exacerbated joint swelling, increased delayed-type hypersensitivity reaction, and increased histopathological scores of arthritis. Intraarticular administration of exogenous IFN-γ at induction of AIA significantly suppressed these acute aggravation effects. Stimulated cells isolated from lymph nodes and spleen of IFN-γ−/− AIA mice showed increased production of IL-2, IL-4, IL-5, IL-6, but most prominently of IL-17. These elevations were paralleled by decreased humoral immune responses, with low serum levels of total and Ag-specific IgG (IgG1, IgG2ab, IgG2b, IgG3). At immunohistology, the knee joints of IFN-γ−/− AIA mice showed massive neutrophil granulocyte infiltration. Treatment with mAbs neutralizing IL-17 diminished the acute inflammation. In vitro, Th cell expansion and production of IL-17 upon restimulation were effectively and dose dependently inhibited by IFN-γ. These results clearly demonstrate that IFN-γ has anti-inflammatory properties during the initial phase of AIA, and indicate that IFN-γ deficiency exerts disease-promoting effects, preferentially via IL-17-modulated pathways.

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“…The antigen-induced arthritis (AIA) model of rheumatoid arthritis (RA) recapitulates features of human RA [44,45]. This model is based on a T cell-mediated joint inflammation.…”

Section: Discussionmentioning

confidence: 99%

Chitosan-based nanogels for selective delivery of photosensitizers to macrophages and improved retention in and therapy of articular joints

Schmitt

Lagopoulos

Käuper³

et al. 2010

Journal of Controlled Release

112

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Macrophages play key roles in inflammatory disorders. Therefore, they are targets of treatments aiming at their local destruction in inflammation sites. However, injection of low molecular mass therapeutics, including photosensitizers, in inflamed joints results in their rapid efflux out of the joints, and poor therapeutic index. To improve selective uptake and increase retention of therapeutics in inflamed tissues, hydrophilic nanogels based on chitosan, of which surface was decorated with hyaluronate and which were loaded with one of three different anionic photosensitizers were developed. Optimal uptake of these functionalized nanogels by murine RAW 264.7 or human THP-1 macrophages as models was achieved after b 4 h incubation, whereas only negligible uptake by murine fibroblasts used as control cells was observed. The uptake by cells and the intracellular localization of the photosensitizers, of the fluorescein-tagged chitosan and of the rhodamine-tagged hyaluronate were confirmed by fluorescence microscopy. Photodynamic experiments revealed good cell photocytotoxicity of the photosensitizers entrapped in the nanogels. In a mouse model of rheumatoid arthritis, injection of free photosensitizers resulted in their rapid clearance from the joints, while nanogel-encapsulated photosensitizers were retained in the inflamed joints over a longer period of time. The photodynamic treatment of the inflamed joints resulted in a reduction of inflammation comparable to a standard corticoid treatment. Thus, hyaluronate-chitosan nanogels encapsulating therapeutic agents are promising materials for the targeted delivery to macrophages and long-term retention of therapeutics in leaky inflamed articular joints.

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Systemic Macrophage Activation in Locally-induced Experimental Arthritis

Cited by 45 publications

References 48 publications

Interferon‐γ protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints

Interferon‐γ protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints

Exacerbation of Antigen-Induced Arthritis in IFN-γ-Deficient Mice As a Result of Unrestricted IL-17 Response

Chitosan-based nanogels for selective delivery of photosensitizers to macrophages and improved retention in and therapy of articular joints

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