ADAM17 substrate release in proximal tubule drives kidney fibrosis

Kefaloyianni, Eirini; Muthu, Muthu Lakshmi; Kaeppler, Jakob; Sun, Xiaoming; Sabbisetti, Venkata; Chalaris, Athena; Rose–John, Stefan; Wong, Eitan; Sagi, Irit; Waikar, Sushrut S.; Rennke, Helmut G.; Humphreys, Benjamin D.; Bonventre, Joseph V.; Herrlich, Andreas

doi:10.1172/jci.insight.87023

Cited by 107 publications

(128 citation statements)

References 69 publications

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“…Previously, it has been shown that the shedding of EGFR ligands induces expression and activation of these same ligands in a feed‐forward loop . Il10 −/− / Rhbdf2 −/− mice showed enhanced expression levels of EGFR ligands, suggesting that RHBDF2/ADAM17‐independent shedding events of EGFR ligands such as TGFA by the related RHBDF1/ADAM17, may be sufficient to induce EGFR ligand expression for epithelial repair in IBD.…”

Section: Discussionmentioning

confidence: 99%

Loss of RHBDF2 results in an early-onset spontaneous murine colitis

Geesala

Schanz

Biggs

et al. 2019

Journal of Leukocyte Biology

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Inflammatory bowel disease (IBD) is a heterogeneous group of inflammation‐mediated pathologies that include Crohn's disease and ulcerative colitis and primarily affects the colon and small intestine. Previous studies have shown that a disintegrin and metalloprotease (ADAM) 17, a membrane‐bound sheddase, capable of cleaving the proinflammatory cytokine TNF and epidermal growth factor receptor ligands, plays a critical role in maintaining gut homeostasis and modulating intestinal inflammation during IBD. Rhomboid 5 homolog 2 (RHBDF2), a catalytically inactive member of the rhomboid family of intramembrane serine proteases, was recently identified as a crucial regulator of ADAM17. Here, we assessed the role of RHBDF2 in the development of colitis in the context of IL10 deficiency. Il10−/−/Rhbdf2−/− mice developed spontaneous colitis and experienced severe weight loss starting at 8 wk of age, without the need for exogenous triggers. Severity of disease pathology in Il10−/−/Rhbdf2−/− mice correlated with a dysbiotic gut microbiota and elevated Th1‐associated immune responses with increased interferon gamma and IL2 production. In addition, Il10−/−/Rhbdf2−/− mice failed to maintain their epithelial cell homeostasis, although the intestinal epithelial barrier of Rhbdf2−/− mice is intact and loss of Rhbdf2 did not significantly exacerbate sensitivity to dextran sulfate sodium‐induced colitis, suggesting differences in the underlying disease pathway of intestinal inflammation in this model. Taken together, our results demonstrate a critical regulatory role for RHBDF2 in the maintenance of the unique homeostasis between intestinal microbiota and host immune responses in the gut that is dysregulated during the pathogenesis of IBD.

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Section: Discussionmentioning

confidence: 99%

Loss of RHBDF2 results in an early-onset spontaneous murine colitis

Geesala

Schanz

Biggs

et al. 2019

Journal of Leukocyte Biology

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“…The common regulator of TNF-α and EGFR ligands, ADAM17, has been considered as a potential therapeutic target for chronic kidney diseases, particularly progressive fibrosis (15)(16)(17). In diseased Fcgr2b -/-kidneys, both ADAM17 and iRhom2 were upregulated, and iRhom2 was overexpressed in the kidneys of LN patients.…”

Section: Rhbdf2mentioning

confidence: 99%

“…Although blocking ADAM17 could simultaneously shut down multiple pathogenic pathways and has been proposed for treating chronic kidney diseases not related to LN (15)(16)(17), there are substantial concerns about therapeutically targeting ADAM17, mainly because ADAM17 has an essential role in protecting the skin and intestinal barrier through activating the EGFR pathway (18,19). Indeed, mice lacking Adam17 die at birth due to defects in EGFR signaling, and individuals with ADAM17 mutation or those treated with EGFR inhibitors display skin and intestinal inflammation (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

Qing¹,

Chinenov²,

Redecha³

et al. 2018

Journal of Clinical Investigation

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“…Methods: 502 SLE patients were assessed for serum IFNa level using a biological functional assay(1). Remission was defined by the absence of clinical manifestation of lupus activity (clinical SELENA-SLEDAI = 0) and a prednisone intake £ 5 mg/day (2). Patients in remission were subsequently followed for one year.…”

mentioning

confidence: 99%

“…Interestingly, AREG expression was shown to be one of the most highly upregulated transcripts in peripheral blood leukocytes of patient with systemic lupus erythematosus (SLE) [1]. The functional role of AREG in SLE, and inflammation in general, remains unclear to date and both, pro-and anti-inflammatory functions have been postulated [2,3]. Objectives: Our aim was to investigate the role of AREG in the mouse model of pristane induced lupus (PIL) with particular focus on lupus nephritis (LN).…”

mentioning

confidence: 99%

Thu0227 biological Monitoring of Remission in Systemic Lupus Erythematosus: Abnormal Serum Interferon-Alpha Levels Predict Relapse

Mouriès-Martin¹,

Mathian²,

Devilliers

et al. 2019

Poster Presentations

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Background:Remission and relapses prevention are the main objectives of the treatment of Systemic Lupus Erythematosus (SLE). Interferon alpha (IFNα) is a key cytokine in SLE, but its usefulness for the definition of remission and for the prediction of flare has not been validated in clinical practice.Objectives:To study the association between serum IFNα level, remission and risk of relapse.Methods:502 SLE patients were assessed for serum IFNα level using a biological functional assay(1). Remission was defined by the absence of clinical manifestation of lupus activity (clinical SELENA-SLEDAI = 0) and a prednisone intake ≤ 5 mg/day(2). Patients in remission were subsequently followed for one year. The SELENA-SLEDAI Flare Index was used to identify SLE flare. Uni- and multivariable analyses were performed to define disease parameters associated with serum IFNα positivity in patients in remission at baseline. Survival curve analysis, log-rank tests and Hazard Ratios (HR) were calculated to evaluate the risk of flare depending on IFNα, dsDNA Abs and C3 levels at baseline.Abstract THU0227 – Figure 1Results:345 samples were obtained from patients in remission. 28.6% of the patients in clinical remission on treatment (requiring clinical SELENA-SLEDAI = 0, positive anti-dsDNA antibodies and/or C3 decrease and prednisone intake 1 – 5 mg/day) had an abnormal serum IFNα level, compared to 6.5% of the patients in complete remission on treatment (requiring clinical SELENA-SLEDAI = 0, no anti-dsDNA antibodies nor C3 decrease and prednisone intake 1 – 5 mg/day). In patients in remission, high serum IFNα levels at baseline were associated in multivariable analysis with the positivity of anti-dsDNA Abs (HR 3.4 [95%CI 1.6-7.2], p=0.0001) and anti-RNP Abs (HR 3.2 [95%CI 1.5-6.8], p=0.0002). In patients in remission, high serum IFNα level at baseline was a significant and independent risk factor of lupus flare (HR=4.8 [95%CI 2.3-9.7], p<0.0001). Low C3 was also associated with the risk of relapse with a HR=3.2 [95%CI 1.4-7.0], p=0.005, but positive anti-dsDNA Abs was not (HR=1.8 [95%CI 0.9-3.6], p=0.1).Conclusion:A large number of SLE patients in remission display abnormal levels of serum IFNα. Abnormal levels of serum IFNα in patients in remission were significantly associated with positive anti-dsDNA and anti-RNP Abs and were an independent predictive biomarker of lupus flare in the following year. Adding serum IFNα to the routine laboratory assessments perform in patient in remission could help clinicians to identify a subgroup of SLE patient clinically in remission but serologically active and at higher risk of relapse.References:[1] Mathian A, et al. Monitoring disease activity in systemic lupus erythematosus with single-molecule array digital ELISA quantification of serum interferon-α. Arthritis Rheumatol Hoboken NJ.2018Dec3;[2] Vollenhoven R, et al. A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS). Ann Rheum Dis. 2017Mar1;76(3):554–61.Disclosu...

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ADAM17 substrate release in proximal tubule drives kidney fibrosis

Cited by 107 publications

References 69 publications

Loss of RHBDF2 results in an early-onset spontaneous murine colitis

Loss of RHBDF2 results in an early-onset spontaneous murine colitis

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

Thu0227 biological Monitoring of Remission in Systemic Lupus Erythematosus: Abnormal Serum Interferon-Alpha Levels Predict Relapse

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