iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

Qing, Xiaoping; Chinenov, Yurii; Redecha, Patricia; Madaio, Michael P.; Roelofs, Joris J. T. H.; Farber, Gregory; Issuree, Priya D.; Donlin, Laura T.; Mcllwain, David R.; Mak, Tak W.; Blobel, Carl P.; Salmon, Jane E.

doi:10.1172/jci97650

Cited by 72 publications

(51 citation statements)

References 78 publications

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“…Recent studies have shown that RHBDF2 is critical for the development of inflammation and for tissue‐remodeling in a mouse model of lupus nephritis and that mice lacking RHBDF2 are protected from rheumatoid arthritis, similar to mice lacking ADAM17 in myeloid cells . Although these studies confirm that RHBDF2 plays a significant role in both autoimmune diseases and that RHBDF2 is involved in TNF‐dependent septic shock, the role of RHBDF2 in IBD has only been perfunctorily explored …”

Section: Introductionmentioning

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: Introductionmentioning

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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“…Our data provide relevance to these findings in human disease and a mechanistic understanding of the cellular crosstalk program involving growth factors in RA joints. Furthermore, considerable evidence implicates TNF and HBEGF as pathologic drivers of kidney disease in the autoimmune condition lupus ( 61, 62 ). Thus, linked TNF and EGFR responses may be a unifying and targetable feature in tissues affected by disparate autoimmune conditions.…”

Section: Resultsmentioning

confidence: 99%

HBEGF⁺macrophages identified in rheumatoid arthritis promote joint tissue invasiveness and are reshaped differentially by medications

Kuo

Ding

Cohn

et al. 2019

Preprint

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Macrophages tailor their function to the signals found in tissue microenvironments, taking on a wide spectrum of phenotypes. In human tissues, a detailed understanding of macrophage phenotypes is limited. Using single-cell RNA-sequencing, we define distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and shaped by resident fibroblasts and the cytokine TNF. These macrophages promote fibroblast invasiveness in an EGF receptor dependent manner, indicating that inflammatory intercellular crosstalk reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo tissue assay, the HBEGF+ inflammatory macrophage is targeted by several anti-inflammatory RA medications, however, COX inhibition redirects it towards a different inflammatory phenotype that is also expected to perpetuate pathology. These data highlight advances in understanding the pathophysiology and drug mechanisms in chronic inflammatory disorders can be achieved by focusing on macrophage phenotypes in the context of complex interactions in human tissues.One Sentence SummaryA newly identified human macrophage phenotype from patients with the autoimmune condition RA is found to promote joint tissue invasiveness and demonstrates variable sensitivities to anti-inflammatory medications used to treat the disease.

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“…It therefore remains to be determined if other iRhom2‐dependent processes in the cell might be involved in mediating the stability of STING and MAVS as opposed to a direct role of iRhom2 itself. Moreover, the lack of iRhom2 does not affect STING signaling or the type I IFN pathway in a spontaneous lupus mouse model . Unlike initially proposed, it has now been demonstrated that iRhom2 is not restricted to the ER and Golgi apparatus but can translocate to the cell surface, where for instance, it modulates proteolytic activity of ADAM17 …”

Section: Biological Functions Of Irhomsmentioning

confidence: 87%

“…IC depositions in organs trigger the homing of various immune cells such as neutrophils and monocytes, and can also trigger the activation of ADAM17 and release of TNF from Mϕs . Furthermore, expression of EGFR ligands such as HBEGF is drastically up‐regulated in the glomerular crescents of LN patients’ kidneys and strongly colocalizes with Mϕs in the interstitium of LN patients . Both the EFGR and TNF pathway have been implicated in pathogenesis of kidney disease in lupus, although their epistatic relationship remained undetermined …”

Section: Irhoms In Autoimmune and Systemic Inflammatory Diseasesmentioning

confidence: 99%

“…In a recent study, using a Fc‐gamma receptor IIB ( Fcγr2b )‐deficient mouse model of lupus, Qing et al. demonstrated that iRhom2 deficiency protects Fcγr2b ‐deficient mice from severe kidney damage likely due to attenuated TNF and EGFR signaling and demonstrated a novel mechanism by which TNF transactivates the EGFR pathway . Deficiency of Fcγr2b in mice leads to a breakdown in tolerance and the development of lupus‐like syndromes, including production of anti‐double‐stranded DNA (anti‐dsDNA) Abs and LN and 50–60% mortality by 8 to 9 months of age .…”

Section: Irhoms In Autoimmune and Systemic Inflammatory Diseasesmentioning

confidence: 99%

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Novel functions of inactive rhomboid proteins in immunity and disease

Geesala

Issuree

Maretzky

2019

Journal of Leukocyte Biology

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iRhoms are related to a family of intramembrane serine proteinases called rhomboids but lack proteolytic activity. In mammals, there are two iRhoms, iRhom1 and iRhom2, which have similar domain structures and overlapping specificities as well as distinctive functions. These catalytically inactive rhomboids are essential regulators for the maturation and trafficking of the disintegrin metalloprotease ADAM17 from the endoplasmic reticulum to the cell surface, and are required for the cleavage and release of a variety of membrane-associated proteins, including the IL-6 receptor, L-selectin, TNF, and EGFR ligands. iRhom2-dependent regulation of ADAM17 function has been recently implicated in the development and progression of several autoimmune diseases including rheumatoid arthritis, lupus nephritis, as well as hemophilic arthropathy. In this review, we discuss our current understanding of iRhom biology, their implications in autoimmune pathologies, and their potential as therapeutic targets. K E Y W O R D Sa disintegrin and metalloprotease 17 (ADAM17), epidermal growth factor receptor (EGFR), inactive rhomboid 1 (iRHOM1), inactive rhomboid 2 (iRHOM2), rhomboid 5 homolog 1 (RHBDF1), rhomboid 5 homolog 2 (RHBDF2), tumor necrosis factor (TNF) 1 L-selectin from leukocytes and has key roles in their recruitment to sites of inflammation. 10 Moreover, ADAM17 has a wide range of different substrates, 11 including the IL-6 receptor (IL6R), which has important roles in IL6R-dependent pathologies such as multiple myeloma, prostate cancer, and RA. 12,13 The rhomboid 5 homolog proteins iRhom1 and iRhom2 (also known as RHBDF1 and RHBDF2) are proteolytically inactive members of the rhomboid family and act as key regulators of ADAM17-dependent

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iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

Cited by 72 publications

References 78 publications

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

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

HBEGF⁺macrophages identified in rheumatoid arthritis promote joint tissue invasiveness and are reshaped differentially by medications

Novel functions of inactive rhomboid proteins in immunity and disease

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iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

Cited by 72 publications

References 78 publications

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

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

HBEGF+macrophages identified in rheumatoid arthritis promote joint tissue invasiveness and are reshaped differentially by medications

Novel functions of inactive rhomboid proteins in immunity and disease

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HBEGF⁺macrophages identified in rheumatoid arthritis promote joint tissue invasiveness and are reshaped differentially by medications