ArticleThe Journal of clinical investigation2013
iRHOM2 is a critical pathogenic mediator of inflammatory arthritis.
Article in The Journal of clinical investigation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 106 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
106 citing papers in PubMed, 166 citations in OpenAlex.
- Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease.Nature immunology · 2022Trial
- Review
- Deficiency of Inactive Rhomboid Protein 2 (iRhom2) Attenuates Macrophage Atherogenicity.Biology · 2026Article
- Structural basis for ADAM17 activation by the iRhom1 pseudoprotease.Cell reports · 2026Article
- iRhom2 deletion protects against diabetic neuropathy by suppressing neuroinflammation.The Journal of pharmacology and experimental therapeutics · 2026Article
- TACE reprograms RANKL-mediated differentiation of macrophages by activating the non-canonical pathway of IRF3.bioRxiv : the preprint server for biology · 2026Article
- iRhom2 regulates HMGB1 secretion to modulate inflammation and hepatocyte senescence in an in vitro model of ischemia-reperfusion injury.Cell death & disease · 2026Article
- Multi-cohort meta-analysis, single-cell and Mendelian randomization analyses with experimental validation identify RHBDF2 as a shared mediator of ulcerative colitis and blood-brain barrier disruption.Frontiers in synaptic neuroscience · 2026Article
- RHBDF2 governs microglial neuroinflammation during cerebral ischemia-reperfusion injury and is positively regulated by the m6A reader YTHDF1.Molecular medicine (Cambridge, Mass.) · 2025Article
- Holding Out for a Model: Rhomboid Superfamily in Vertebrate Development and Disease.Journal of cellular physiology · 2025Review
- Structural insights into the activation and inhibition of the ADAM17-iRhom2 complex.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The late-onset Alzheimer's disease risk factor RHBDF2 is a modifier of microglial TREM2 proteolysis.Life science alliance · 2025Article
- Biomaterials for Modulating the Immune Microenvironment in Rheumatoid Arthritis.BME frontiers · 2025Review
- Increased Expression of Inactive Rhomboid Protein 2 in Circulating Monocytes after Acute Myocardial Infarction.Journal of cardiovascular translational research · 2024Article
- The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus.eLife · 2024Article
- Downregulation of the metalloproteinases ADAM10 or ADAM17 promotes osteoclast differentiation.Cell communication and signaling : CCS · 2024Article
- Role of iRhom2 in Olfaction: Implications for Odorant Receptor Regulation and Activity-Dependent Adaptation.International journal of molecular sciences · 2024Article
- iRhom2 regulates ectodomain shedding and surface expression of the major histocompatibility complex (MHC) class I.Cellular and molecular life sciences : CMLS · 2024Article
- Pathological mutations reveal the key role of the cytosolic iRhom2 N-terminus for phosphorylation-independent 14-3-3 interaction and ADAM17 binding, stability, and activity.Cellular and molecular life sciences : CMLS · 2024Article
- Are peptidomimetics the compounds of choice for developing new modulators of the JAK-STAT pathway?Frontiers in immunology · 2024Review
46 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 6 institutions in 4 countries.
Funding
Abstract
iRHOM2, encoded by the gene Rhbdf2, regulates the maturation of the TNF-α convertase (TACE), which controls shedding of TNF-α and its biological activity in vivo. TACE is a potential target to treat TNF-α-dependent diseases, such as rheumatoid arthritis, but there are concerns about potential side effects, because TACE also protects the skin and intestinal barrier by activating EGFR signaling. Here we report that inactivation of Rhbdf2 allows tissue-specific regulation of TACE by selectively preventing its maturation in immune cells, without affecting its homeostatic functions in other tissues. The related iRHOM1, which is widely expressed, except in hematopoietic cells, supported TACE maturation and shedding of the EGFR ligand TGF-α in Rhbdf2-deficient cells. Remarkably, mice lacking Rhbdf2 were protected from K/BxN inflammatory arthritis to the same extent as mice lacking TACE in myeloid cells or Tnfa-deficient mice. In probing the underlying mechanism, we found that two main drivers of K/BxN arthritis, complement C5a and immune complexes, stimulated iRHOM2/TACE-dependent shedding of TNF-α in mouse and human cells. These data demonstrate that iRHOM2 and myeloid-expressed TACE play a critical role in inflammatory arthritis and indicate that iRHOM2 is a potential therapeutic target for selective inactivation of TACE in myeloid cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.