Cutting Edge: Mast Cells Express IL-17A in Rheumatoid Arthritis Synovium

Hueber, Axel J.; Asquith, Darren L.; Miller, Ashley M.; Reilly, Jim; Kerr, Shauna; Leipe, Jan; Melendez, Alirio J.; McInnes, Iain B.

doi:10.4049/jimmunol.0903566

Cited by 330 publications

(297 citation statements)

References 22 publications

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“…The consequences of this event could be now evaluated in diseases where MCs represent a potent source of proinflammatory cytokines and exposure to AhR ligands is likely to occur (38). For instance, MCs alone or together with other non-T immune cells are predominant IL-17 + cells in psoriatic lesions in human skin (25), in atherosclerotic plaques (39), as well as in rheumatoid arthritis, osteoarthritis, and spondyloarthritis synovium (24,26,40). Human MCs require the Th17 lineage-defining transcription factor Rorc to produce IL-17 in response to different stimuli (24).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, MCs alone or together with other non-T immune cells are predominant IL-17 + cells in psoriatic lesions in human skin (25), in atherosclerotic plaques (39), as well as in rheumatoid arthritis, osteoarthritis, and spondyloarthritis synovium (24,26,40). Human MCs require the Th17 lineage-defining transcription factor Rorc to produce IL-17 in response to different stimuli (24). In this study, we were not able to detect Rorc in both unstimulated and FICZ-stimulated BMMCs (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

“…AhR is widely considered a key factor in driving the fate of Th17 differentiation (5) and in inducing IL-6 production itself (23), whereas MCs represent a potent source of IL-6 and IL-17 in many pathological conditions such as in the synovium in rheumatoid arthritis, in osteoarthritis, and in psoriatic lesions (24)(25)(26). On these bases, we investigated whether direct exposure to FICZ could drive MCs to release IL-6 and IL-17.…”

Section: Ficz Stimulation Sets the Stage For The Proinflammatory Milimentioning

confidence: 99%

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The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

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Frossi

Calvaruso

et al. 2012

The Journal of Immunology

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The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor whose activity is modulated by xenobiotics as well as physiological ligands. These compounds may modulate inflammatory responses and contribute to the rising prevalence of allergic diseases observed in industrialized countries. Mast cells (MCs), located within tissues at the boundary of the external environment, represent a potential target of AhR ligands. In this study, we report that murine and human MCs constitutively express AhR, and its activation by the high-affinity ligand 6-formylindolo[3,2-b]carbazole (FICZ) determines a boost in degranulation. On the contrary, repeated exposure to FICZ inhibits MC degranulation. Accordingly, histamine release, in an in vivo passive systemic anaphylactic model, is exacerbated by a single dose and is attenuated by repetitive stimulation of AhR. FICZ-exposed MCs produce reactive oxygen species and IL-6 in response to cAMP-dependent signals. Moreover, AhR-activated MCs produce IL-17, a critical player in chronic inflammation and autoimmunity, suggesting a novel pathway for MC activation in the pathogenesis of these diseases. Indeed, histological analysis of patients with chronic obstructive pulmonary disease revealed an enrichment in AhR/IL-6 and AhR/IL-17 double-positive MCs within bronchial lamina propria. Thus, tissue-resident MCs could translate external chemical challenges through AhR by modulating allergic responses and contributing to the generation of inflammation-related diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ficz Stimulation Sets the Stage For The Proinflammatory Milimentioning

confidence: 99%

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The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

Sibilano

Frossi

Calvaruso

et al. 2012

The Journal of Immunology

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“…Lymphocytes producing Il-17 belong to a specific lineage (TH17 cells) determined by unique transcription factor profile (ROR-c) and cytokine expression profile (IL-17, TNF, IL-21, IL-22). TH17 cells have shown to stimulate osteoclast differentiation indirectly through IL-17-mediated stimulation of pro-osteoclastogenic molecules, such as RANKL on mesenchymal cells [43]. Because of its potent pro-inflammatory properties, IL-17 is considered as a potential target for the treatment of inflammatory diseases.…”

Section: Il-17a and Il-17fmentioning

confidence: 99%

Effects of inflammatory and anti‐inflammatory cytokines on the bone

Schett

2011

Eur J Clin Investigation

217

161

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“…Th17 cells have been found in the synovial membrane of rheumatoid arthritis patients, albeit not being the most abundant T-cell lineage in inflamed joints [9]. Additionally, mast cells are a source for IL-17 in the joints of patients with rheumatoid arthritis [10]. In contrast, cytokines linked to Th2 cells such as IL-4 effectively block osteoclast differentiation and also IL-12 and IFN-g, which are the cytokine signature of Th1 cells are potent inhibitors of osteoclasts [11][12][13].…”

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confidence: 99%

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

et al. 2011

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Tumour necrosis factor alpha (TNF-a) is a major inducer for inflammation and bone loss. Here, we investigated whether interleukin (IL)-17 plays a role in TNF-a-mediated inflammation and bone resorption. Human TNF-a transgenic (hTNFtg) mice were treated with a neutralizing anti-IL-17A antibody and assessed for inflammation, cartilage and bone damage. T-cell transcription factors and lymphokine patterns were measured in the LNs. IL-17A inhibition in the absence of IL-1 was also evaluated by treating hTNFtg/IL-1 À/À mice with an IL-17A neutralizing antibody. IL-17A neutralization had only minor effects on TNF-a-induced inflammation but effectively reduced local and systemic bone loss by blocking osteoclast differentiation in vivo. Effects were based on a shift to bone-protective T-cell responses such as enhanced Th2 differentiation, IL-4 and IL-12 expression and Treg cell numbers. Whereas inflammation in hTNFtg/IL-1 À/À mice was highly sensitive to IL-17A blockade, no shift in the T-cell lineages and no additional benefit on bone mass were observed in response to IL-17A neutralization. We thus conclude that IL-17A is a key mediator of TNF-a-induced bone loss by closely interacting with IL-1 in blocking bone protective T-cell responses.Key words: Arthritis . Cytokine . IL-17 . Osteoclast . T cells IntroductionBone is continuously remodelled in life by the interaction between bone resorbing cells, termed osteoclasts, with boneforming cells, termed osteoblasts [1]. Bone resorption and bone formation are usually in physiological balance, maintaining a stable bone mass. An imbalance between bone resorption and bone formation leads to bone loss and several factors such as age, oestrogen deficiency or drug therapy alter this fine balance between osteoclasts and osteoblasts in favour of the former. Immune activation and inflammation is one the pivotal condi-Ã These authors contributed equally to this work. 413tions perturbing this fine balance of bone remodelling ultimately leading to enhanced bone loss [2]. Autoimmune inflammatory diseases, such as chronic arthritis are characterized by activation of the innate and adaptive immune system eliciting profound local and systemic bone loss. Progressive destruction of the joints is associated with pain, functional impairment and low quality of life. In addition, loss of systemic bone mass causes osteoporosis and increased fracture risk in patients with inflammatory arthritis [3]. This tight link between inflammation and bone loss is mediated by inducible expression of factors, such as M-CSF and RANKL, which are essential for osteoclast differentiation [4]. In addition, inflammatory cytokines produced by monocytes and resident mesenchymal cells are of key importance for osteoclast formation, as they regulate expression of RANKL and also sensitize monocytes for osteoclast differentiation. In this context, TNF-a, and IL-1 are of particular key importance for osteoclast formation and bone resorption in inflammatory tissue [5,6].Aside from classical pro-inflammatory mediators like ...

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Cutting Edge: Mast Cells Express IL-17A in Rheumatoid Arthritis Synovium

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Cited by 330 publications

References 22 publications

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

Effects of inflammatory and anti‐inflammatory cytokines on the bone

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

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