Cutting Edge: ABIN-1 Protects against Psoriasis by Restricting MyD88 Signals in Dendritic Cells

Callahan, Joseph A.; Hammer, Gianna; Agelides, Alexander; Duong, Bao; Oshima, Shigeru; North, Jeffrey P.; Advincula, Rommel; Shifrin, Nataliya; Truong, Hong-An; Paw, Jonathan S.; Barrera, Julio; DeFranco, Anthony L.; Rosenblum, Michael D.; Malynn, Barbara A.; Ma, Averil

doi:10.4049/jimmunol.1203335

Cited by 51 publications

(61 citation statements)

References 29 publications

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“…Psoriasis is linked to several inflammatory cytokines, with a predominant role for IL-17A signaling, based in part on the success of anti-IL-17A and anti-IL-17RA biologic drugs (26,(37)(38)(39). Therefore, the idea that ABIN-1 is both a tonic inhibitor of inflammation and a negative regulator of IL-17 signaling fits well with our data and with findings in preclinical mouse models and human studies (10)(11)(12).…”

Section: Discussionsupporting

confidence: 87%

“…Luciferase assays were performed as described (7,14). Small interfering RNAs (siRNAs) were from Dharmacon (GE, Lafayette, CO): Tnip1 (ABIN-1) (L-047652-01), Tnfaip3 (A20) (L-058907-02), and nontargeting mock (D-001810- [10][11][12][13][14][15][16][17][18][19][20]. siRNA transfections were performed 48 h prior to stimulation.…”

Section: Abs and Reagentsmentioning

confidence: 99%

“…The A20-binding inhibitor of NF-kB activation 1 (ABIN-1) is an A20-binding protein coded by the TNIP1 gene. ABIN-1 single nucleotide polymorphisms are associated with psoriasis in human genome-wide association analyses (8)(9)(10)(11). Additionally, mice with keratinocytes lacking ABIN-1 are more sensitive to imiquimod-induced dermatitis, a model of psoriasis (12).…”

Section: Introductionmentioning

confidence: 99%

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IL-17 Signaling Triggers Degradation of the Constitutive NF-κB Inhibitor ABIN-1

et al. 2017

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IL-17 activates NF-κB and inducing expression of proinflammatory genes. IL-17 drives disease in autoimmune conditions, and anti-IL-17 antibodies have shown impressive success in the clinic. Although produced by lymphocytes, IL-17 predominantly signals in fibroblasts and epithelial cells. IL-17-driven inflammation is kept in check by negative feedback signaling molecules, including the ubiquitin editing enzyme A20, whose gene TNFΑIP3 is and similarly linked to autoimmune disease susceptibility. Accordingly, we hypothesized that ABIN-1 might play a role in negatively regulating IL-17 signaling activity. Indeed, ABIN-1 enhanced both tonic and IL-17-dependent NF-κB signaling in IL-17-responsive fibroblast cells. Interestingly, the inhibitory activities of ABIN-1 on IL-17 signaling were independent of A20. ABIN-1 is a known NF-κB target gene, and we found that IL-17-induced activation of NF-κB led to enhanced ABIN-1 mRNA expression and promoter activity. Surprisingly, however, the ABIN-1 protein was inducibly degraded following IL-17 signaling in a proteasome-dependent manner. Thus, ABIN-1, acting independently of A20, restricts both baseline and IL-17-induced inflammatory gene expression. We conclude that IL-17-induced signals lead to degradation of ABIN-1, thereby releasing a constitutive cellular brake on NF-κB activation.

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Section: Discussionsupporting

confidence: 87%

Section: Abs and Reagentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IL-17 Signaling Triggers Degradation of the Constitutive NF-κB Inhibitor ABIN-1

et al. 2017

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“…In addition, a strong genetic link with A20 and A20 binding and inhibitor of NF-kB in psoriasis has been reported previously (51,52). Both A20 and A20 binding and inhibitor of NF-kB can bind to linear ubiquitin chains that are specifically generated by LUBAC (53)(54)(55).…”

Section: Ifn-a Increased the Amount Of Lubac And Ameliorated Dermatitmentioning

confidence: 86%

IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex

Tamiya

Terao

Takiuchi

et al. 2014

The Journal of Immunology

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The linear ubiquitin chain assembly complex (LUBAC) ubiquitin ligase complex, composed of HOIL-1L–interacting protein (HOIP), heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), and SHANK-associated RH domain protein, specifically generates linear polyubiquitin chains and is involved in NF-κB activation. Lack of SHANK-associated RH domain protein, which drastically reduces the amount of HOIP and HOIL-1L, causes chronic proliferative dermatitis (cpdm) in mice. Impaired NF-κB activation and augmented apoptosis have been implicated in the pathogenesis of cpdm in mice. In this study, we found that IFN-γ increased the amount of LUBAC by inducing HOIP and HOIL-1L mRNA transcription and enhanced the signal-induced NF-κB activation in embryonic fibroblasts, keratinocytes, and bone marrow–derived macrophages from wild-type and/or cpdm mice; however, IFN-γ failed to augment NF-κB activation in mouse embryonic fibroblasts lacking linear polyubiquitination activity of LUBAC. Moreover, s.c. injection of IFN-γ for 3 wk into the skin of cpdm mice increased the amount of HOIP, suppressed apoptosis, and ameliorated the dermatitis. Inhibition of keratinocyte apoptosis by IFN-γ injection suppressed neutrophil, macrophage, and mast cell infiltration and the amount of TNF-α in the skin of cpdm mice. Similarly, IFN-α also enhanced the amount of HOIP as well as NF-κB activation, inhibited apoptosis, and ameliorated cpdm dermatitis. These results indicate that the IFNs enhance NF-κB activation and ameliorate cpdm dermatitis by augmenting expression of HOIP and HOIL-1L and linear polyubiquitination activity of LUBAC.

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“…9B. In the literature, a frequently used protocol for imiquimod-induced psoriasis-like inflammation is treating mice daily with imiquimod for 1 wk (55,56). To make this model more closely resemble chronic inflammation and to compare with the effect of LL37, in the third model, mouse ears were topically treated with 5% imiquimod cream and 5% thiostrepton gel once per week following the schedule shown in Fig.…”

Section: Thiostrepton Attenunates Ll37-and Imiquimod-induced Psoriasimentioning

confidence: 99%

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

Lai

Yeh

et al. 2015

The Journal of Immunology

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Activation of TLR7–9 has been linked to the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. Thus, therapeutic applications of antagonists of these TLRs for such disorders are being investigated. Bortezomib (Velcade) is a proteasome inhibitor known to suppress activation of these TLRs. To identify novel TLR7–9 inhibitors, we searched the Gene Expression Omnibus database for gene expression profiles of bortezomib-treated cells. These profiles were then used to screen the Connectivity Map database for chemical compounds with similar functions as bortezomib. A natural antibiotic, thiostrepton, was identified for study. Similar to bortezomib, thiostrepton effectively inhibits TLR7–9 activation in cell-based assays and in dendritic cells. In contrast to bortezomib, thiostrepton does not inhibit NF-κB activation induced by TNF-α, IL-1, and other TLRs, and it is less cytotoxic to dendritic cells. Thiostrepton inhibits TLR9 localization in endosomes for activation via two mechanisms, which distinguish it from currently used TLR7–9 inhibitors. One mechanism is similar to the proteasome inhibitory function of bortezomib, whereas the other is through inhibition of endosomal acidification. Accordingly, in different animal models, thiostrepton attenuated LL37- and imiquimod-induced psoriasis-like inflammation. These results indicated that thiostrepton is a novel TLR7–9 inhibitor, and compared with bortezomib, its inhibitory effect is more specific to these TLRs, suggesting the potential therapeutic applications of thiostrepton on immunologic disorders elicited by inappropriate activation of TLR7–9.

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Cutting Edge: ABIN-1 Protects against Psoriasis by Restricting MyD88 Signals in Dendritic Cells

Cited by 51 publications

References 29 publications

IL-17 Signaling Triggers Degradation of the Constitutive NF-κB Inhibitor ABIN-1

IL-17 Signaling Triggers Degradation of the Constitutive NF-κB Inhibitor ABIN-1

IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

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