IRAK4 Kinase Activity Is Required for Th17 Differentiation and Th17-Mediated Disease

Staschke, Kirk A.; Dong, Sucai; Saha, Joy K.; Zhao, Jingyong; Brooks, Nathan; Hepburn, Deena L.; Xia, Jinqi; Gulen, Muhammet F.; Kang, Zizhen; Altuntas, Cengiz Z.; Tuohy, Vincent K.; Gilmour, Raymond; Li, Xiaoxia; Na, Songqing

doi:10.4049/jimmunol.0802361

Cited by 52 publications

(55 citation statements)

References 45 publications

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“…Therefore, ES-62 subversion of signaling via TLR-4, with consequent down-regulation of MyD88, a key signal transducer of the TLR/IL-1 receptor (IL-1R) family (30), would provide a molecular rationale for the observed decrease in Th17 polarization, given that it has recently been reported (31,32) that IL-1R-associated kinase 4 (IRAK-4) and IRAK-1, the downstream effectors of IL-1R/MyD88 signaling, are required for such polarization.…”

Section: Discussionmentioning

confidence: 99%

“…ES-62 can also act directly on CD4ϩ T cells to suppress IL-1-dependent Th17 differentiation, and this likely involves TLR-4-mediated down-regulation of MyD88, leading to uncoupling of IL-1R from IRAK-1/4 signals that are essential for Th17 polarization (31,32). Since MyD88 is a key signal transducer for all TLR family members except for TLR-3 (interestingly, signaling of which is not modulated by ES-62 [19]), the recent finding that Th17 responses and consequent autoimmune pathogenesis are promoted by TLR-2 signaling in vivo (28) suggests that ES-62 may downregulate MyD88 expression as a general mechanism of targeting aberrant Th17 responses and inflammatory disease.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The parasitic helminth product ES‐62 suppresses pathogenesis in collagen‐induced arthritis by targeting the interleukin‐17–producing cellular network at multiple sites

Pineda

McGrath

Smith

et al. 2012

Arthritis & Rheumatism

146

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Objective. Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The parasitic helminth product ES‐62 suppresses pathogenesis in collagen‐induced arthritis by targeting the interleukin‐17–producing cellular network at multiple sites

Pineda

McGrath

Smith

et al. 2012

Arthritis & Rheumatism

146

View full text Add to dashboard Cite

show abstract

“…Furthermore, Irak1 deficiency has not been described in immunodeficient human patients, suggesting that IRAK1 would be a safer therapy target than IRAK4. Irak1-deficient mice are less susceptible to systemic autoimmunity in a congenic lupus model (13) and are resistant against experimental autoimmune encephalomyelitis (14,15), suggesting that IRAK1 plays a nonredundant role on autoimmune and inflammatory diseases. In vitro studies showed that Th17 differentiation is impaired whereas Treg generation is enhanced in Irak1-deficient CD4 + T cells (16).…”

Section: E Ffector Th Cells Producing Inflammatory Cytokines Play An mentioning

confidence: 99%

IRAK1 Drives Intestinal Inflammation by Promoting the Generation of Effector Th Cells with Optimal Gut-Homing Capacity

Heiseke¹,

Jeuk²,

Markota³

et al. 2015

The Journal of Immunology

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IL-1R–associated kinase (IRAK) 1 is an important component of the IL-1R and TLR signaling pathways, which influence Th cell differentiation. In this study, we show that IRAK1 promotes Th17 development by mediating IL-1β–induced upregulation of IL-23R and subsequent STAT3 phosphorylation, thus enabling sustained IL-17 production. Moreover, we show that IRAK1 signaling fosters Th1 differentiation by mediating T-bet induction and counteracts regulatory T cell generation. Cotransfer experiments revealed that Irak1-deficient CD4+ T cells have a cell-intrinsic defect in generating Th1 and Th17 cells under inflammatory conditions in spleen, mesenteric lymph nodes, and colon tissue. Furthermore, IRAK1 expression in T cells was shown to be essential for T cell accumulation in the inflamed intestine and mesenteric lymph nodes. Transcriptome analysis ex vivo revealed that IRAK1 promotes T cell activation and induction of gut-homing molecules in a cell-intrinsic manner. Accordingly, Irak1-deficient T cells failed to upregulate surface expression of α4β7 integrin after transfer into Rag1−/− mice, and their ability to induce colitis was greatly impaired. Lack of IRAK1 in recipient mice provided additional protection from colitis. Therefore, IRAK1 plays an important role in intestinal inflammation by mediating T cell activation, differentiation, and accumulation in the gut. Thus, IRAK1 is a promising novel target for therapy of inflammatory bowel diseases.

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“…Blockade of IL-17A in the absence of IL-1 abrogates TNF-mediated arthritis and bone destruction As IL-1 is an important downstream mediator of TNF-induced bone destruction [6,16] and is also involved in the differentiation of Th17 cells [17], we were interested to test the influence of IL-1, when blocking IL-17A in TNF-a-mediated arthritis. We therefore blocked IL-17 in IL-1 À/À hTNFtg mice, which developed inflammatory arthritis but showed less bone destruction.…”

Section: Il-17a Blockade Modulates T-cell Balance In Tnf-amediated Armentioning

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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IRAK4 Kinase Activity Is Required for Th17 Differentiation and Th17-Mediated Disease

Cited by 52 publications

References 45 publications

The parasitic helminth product ES‐62 suppresses pathogenesis in collagen‐induced arthritis by targeting the interleukin‐17–producing cellular network at multiple sites

The parasitic helminth product ES‐62 suppresses pathogenesis in collagen‐induced arthritis by targeting the interleukin‐17–producing cellular network at multiple sites

IRAK1 Drives Intestinal Inflammation by Promoting the Generation of Effector Th Cells with Optimal Gut-Homing Capacity

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

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