Role Of ADAM17 Research Articles

The Role of ADAM17 in PCOS Pathogenesis: A review Paper

This review primarily focuses on the Role of metalloproteinase (ADAM 17). Gynaecological disease contributes to approximately 4.5% of the worldwide disease burden. Gynecological problems in women of reproductive age are linked to both In terms of diagnosis and treatment. Because there are no defined biomarkers, identifying gynaecological disorders, particularly malignancies, has been difficult in most cases, and histopathological exams remained the gold benchmark. M.M.P.s, ADAMs, and ADAMTSs, as well as their endogenous inhibitors (TIMPs), influence the protease-dependent bioavailability of local niche components. ADAM 17 has been implicated in various pathological processes, including inflammatory response, cardiovascular disease, and, recently, ovarian dysfunction. Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and is characterised by chronic anovulation, insulin resistance, and increased prevalence of cardiovascular risk factors. So far, the PCOS has not assessed the circulating levels of MMPs and their tissue inhibitors (TIMPs). This review will concentrate on the Role of (ADAM17) in regulating gynaecological disorder (PCOS) and their consequent modulation for therapeutic intervention.

New insights into the function and pathophysiology of the ectodomain sheddase A Disintegrin And Metalloproteinase 10 (ADAM10).

The "A Disintegrin And Metalloproteinase 10" (ADAM10) has gained considerable attention due to its discovery as an "α-secretase" involved in the non-amyloidogenic processing of the amyloid precursor protein, thereby possibly preventing the excessive generation of the amyloid beta peptide, which is associated with the pathogenesis of Alzheimer's Disease. ADAM10 was found to exert many additional functions, cleaving about 100 different membrane proteins. ADAM10 is involved in many pathophysiological conditions, ranging from cancer and autoimmune disorders to neurodegeneration and inflammation. ADAM10 cleaves its substrates close to the plasma membrane, a process referred to as ectodomain shedding. This is a central step in the modulation of the functions of cell adhesion proteins and cell surface receptors. ADAM10 activity is controlled by transcriptional and posttranslational events. The interaction of ADAM10 with tetraspanins and the way they functionally and structurally depend on each other is another topic of interest. In this review, we will summarize findings on how ADAM10 is regulated and what is known about the biology of the protease. We will focus on novel aspects of the molecular biology and pathophysiology of ADAM10 that were previously poorly covered, such as the role of ADAM10 on extracellular vesicles, its contribution to virus entry, its involvement in cardiac disease, cancer, inflammation and immune regulation. ADAM10 has emerged as a regulator controlling cell surface proteins during development and in adult life. Its involvement in disease states suggests that ADAM10 may be exploited as a therapeutic target to treat conditions associated with a dysfunctional proteolytic activity.

Semaphorin 4B is an ADAM17-cleaved adipokine that inhibits adipocyte differentiation and thermogenesis

ObjectiveThe metalloprotease ADAM17 (also called TACE) plays fundamental roles in homeostasis by shedding key signaling molecules from the cell surface. Although its importance for the immune system and epithelial tissues is well-documented, little is known about the role of ADAM17 in metabolic homeostasis. The purpose of this study was to determine the impact of ADAM17 expression, specifically in adipose tissues, on metabolic homeostasis. MethodsWe used histopathology, molecular, proteomic, transcriptomic, in vivo integrative physiological and ex vivo biochemical approaches to determine the impact of adipose tissue-specific deletion of ADAM17 upon adipocyte and whole organism metabolic physiology. ResultsADAM17adipoq-creΔ/Δ mice exhibited a hypermetabolic phenotype characterized by elevated energy consumption and increased levels of adipocyte thermogenic gene expression. On a high fat diet, these mice were more thermogenic, while exhibiting elevated expression levels of genes associated with lipid oxidation and lipolysis. This hypermetabolic phenotype protected mutant mice from obesogenic challenge, limiting weight gain, hepatosteatosis and insulin resistance. Activation of beta-adrenoceptors by the neurotransmitter norepinephrine, a key regulator of adipocyte physiology, triggered the shedding of ADAM17 substrates, and regulated ADAM17 expression at the mRNA and protein levels, hence identifying a functional connection between thermogenic licensing and the regulation of ADAM17. Proteomic studies identified Semaphorin 4B (SEMA4B), as a novel ADAM17-shed adipokine, whose expression is regulated by physiological thermogenic cues, that acts to inhibit adipocyte differentiation and dampen thermogenic responses in adipocytes. Transcriptomic data showed that cleaved SEMA4B acts in an autocrine manner in brown adipocytes to repress the expression of genes involved in adipogenesis, thermogenesis, and lipid uptake, storage and catabolism. ConclusionsOur findings identify a novel ADAM17-dependent axis, regulated by beta-adrenoceptors and mediated by the ADAM17-cleaved form of SEMA4B, that modulates energy balance in adipocytes by inhibiting adipocyte differentiation, thermogenesis and lipid catabolism.

The role of ADAM17 in cerebrovascular and cognitive function in the APP/PS1 mouse model of Alzheimer's disease.

The disintegrin and metalloproteinase 17 (ADAM17) exhibits α-secretase activity, whereby it can prevent the production of neurotoxic amyloid precursor protein-α (APP). ADAM17 is abundantly expressed in vascular endothelial cells and may act to regulate vascular homeostatic responses, including vasomotor function, vascular wall morphology, and formation of new blood vessels. The role of vascular ADAM17 in neurodegenerative diseases remains poorly understood. Here, we hypothesized that cerebrovascular ADAM17 plays a role in the pathogenesis of Alzheimer's disease (AD). We found that 9-10 months old APP/PS1 mice with b-amyloid accumulation and short-term memory and cognitive deficits display a markedly reduced expression of ADAM17 in cerebral microvessels. Systemic delivery and adeno-associated virus (AAV)-mediated re-expression of ADAM17 in APP/PS1 mice improved cognitive functioning, without affecting b-amyloid plaque density. In isolated and pressurized cerebral arteries of APP/PS1 mice the endothelium-dependent dilation to acetylcholine was significantly reduced, whereas the vascular smooth muscle-dependent dilation to the nitric oxide donor, sodium nitroprusside was maintained when compared to WT mice. The impaired endothelium-dependent vasodilation of cerebral arteries in APP/PS1 mice was restored to normal level by ADAM17 re-expression. The cerebral artery biomechanical properties (wall stress and elasticity) and microvascular network density was not affected by ADAM17 re-expression in the APP/PS1 mice. Additionally, proteomic analysis identified several differentially expressed molecules involved in AD neurodegeneration and neuronal repair mechanisms that were reversed by ADAM17 re-expression. Thus, we propose that a reduced ADAM17 expression in cerebral microvessels impairs vasodilator function, which may contribute to the development of cognitive dysfunction in APP/PS1 mice, and that ADAM17 can potentially be targeted for therapeutic intervention in AD.

The role of ADAM10 in astrocytes: Implications for Alzheimer's disease.

Much of the early research into AD relies on a neuron-centric view of the brain, however, evidence of multiple altered cellular interactions between glial cells and the vasculature early in AD has been demonstrated. As such, alterations in astrocyte function are widely recognized a contributing factor in the pathogenesis of AD. The processes by which astrocytes may be involved in AD make them an interesting target for therapeutic intervention, but in order for this to be most effective, there is a need for the specific mechanisms involving astrocyte dysfunction to be investigated. "α disintegrin and metalloproteinase" 10 (ADAM10) is capable of proteolytic cleavage of the amyloid precursor protein which prevents amyloid-β generation. As such ADAM10 has been identified as an interesting enzyme in AD pathology. ADAM10 is also known to play a role in a significant number of cellular processes, most notable in notch signaling and in inflammatory processes. There is a growing research base for the involvement of ADAM10 in regulating astrocytic function, primarily from an immune perspective. This review aims to bring together available evidence for ADAM10 activity in astrocytes, and how this relates to AD pathology.

HIV-Associated Insults Modulate ADAM10 and Its Regulator Sirtuin1 in an NMDA Receptor-Dependent Manner.

Neurologic deficits associated with human immunodeficiency virus (HIV) infection impact about 50% of persons with HIV (PWH). These disorders, termed HIV-associated neurocognitive disorders (HAND), possess neuropathologic similarities to Alzheimer’s disease (AD), including intra- and extracellular amyloid-beta (Aβ) peptide aggregates. Aβ peptide is produced through cleavage of the amyloid precursor protein (APP) by the beta secretase BACE1. However, this is precluded by cleavage of APP by the non-amyloidogenic alpha secretase, ADAM10. Previous studies have found that BACE1 expression was increased in the CNS of PWH with HAND as well as animal models of HAND. Further, BACE1 contributed to neurotoxicity. Yet in in vitro models, the role of ADAM10 and its potential regulatory mechanisms had not been examined. To address this, primary rat cortical neurons were treated with supernatants from HIV-infected human macrophages (HIV/MDMs). We found that HIV/MDMs decreased levels of both ADAM10 and Sirtuin1 (SIRT1), a regulator of ADAM10 that is implicated in aging and in AD. Both decreases were blocked with NMDA receptor antagonists, and treatment with NMDA was sufficient to induce reduction in ADAM10 and SIRT1 protein levels. Furthermore, decreases in SIRT1 protein levels were observed at an earlier time point than the decreases in ADAM10 protein levels, and the reduction in SIRT1 was reversed by proteasome inhibitor MG132. This study indicates that HIV-associated insults, particularly excitotoxicity, contribute to changes of APP secretases by downregulating levels of ADAM10 and its regulator.

NGF/TRKA Promotes ADAM17-Dependent Cleavage of P75 in Ovarian Cells: Elucidating a Pro-Tumoral Mechanism.

Nerve growth factor (NGF) and its high-affinity receptor TRKA are overexpressed in epithelial ovarian cancer (EOC) displaying a crucial role in the disease progression. Otherwise, NGF interacts with its low-affinity receptor P75, activating pro-apoptotic pathways. In neurons, P75 could be cleaved by metalloproteinases (α and γ-secretases), leading to a decrease in P75 signaling. Therefore, this study aimed to evaluate whether the shedding of P75 occurs in EOC cells and whether NGF/TRKA could promote the cleavage of the P75 receptor. The immunodetection of the α-secretase, ADAM17, TRKA, P75, and P75 fragments was assessed by immunohisto/cytochemistry and Western blot in biopsies and ovarian cell lines. The TRKA and secretases’ inhibition was performed using specific inhibitors. The results show that P75 immunodetection decreased during EOC progression and was negatively correlated with the presence of TRKA in EOC biopsies. NGF/TRKA increases ADAM17 levels and the fragments of P75 in ovarian cells. This effect is abolished when cells are previously treated with ADAM17, γ-secretase, and TRKA inhibitors. These results indicate that NGF/TRKA promotes the shedding of P75, involving the activation of secretases such as ADAM17. Since ADAM17 has been proposed as a screening marker for early detection of EOC, our results contribute to understanding better the role of ADAM17 and NGF/TRKA in EOC pathogenesis, which includes the NGF/TRKA-mediated cleavage of P75.

Exosome-Derived ADAM17 Promotes Liver Metastasis in Colorectal Cancer.

Exosomes derived from cancer cells are deemed important drivers of pre-metastatic niche formation at distant organs, but the underlying mechanisms of their effects remain largely unknow. Although the role of ADAM17 in cancer cells has been well studied, the secreted ADAM17 effects transported via exosomes are less understood. Herein, we show that the level of exosome-derived ADAM17 is elevated in the serum of patients with metastatic colorectal cancer as well as in metastatic colorectal cancer cells. Furthermore, exosomal ADAM17 was shown to promote the migratory ability of colorectal cancer cells by cleaving the E-cadherin junction. Moreover, exosomal ADAM17 overexpression as well as RNA interference results highlighted its function as a tumor metastasis-promoting factor in colorectal cancer in vitro and in vivo. Taken together, our current work suggests that exosomal ADAM17 is involved in pre-metastatic niche formation and may be utilized as a blood-based biomarker of colorectal cancer metastasis.

ADAM15 correlates with prognosis, immune infiltration and apoptosis in hepatocellular carcinoma.

ADAM15 is highly expressed in malignant tumors and is correlated with tumor progression. However, the role of ADAM15 in hepatocellular carcinoma (HCC) remains unclear. In the study, our results indicated that ADAM15 was highly expressed in HCC tissues and cells compared with corresponding tissues and liver cells. Overexpression of ADAM15 was linked to poor prognosis, and was an independent risk factor for HCC prognosis. Besides, analysis of immune infiltration indicated that ADAM15 expression was related to tumor infiltrating lymphocytes based on the TIMER, TISIDB and GEPIA databases. Many immune checkpoint gene expression was associated with ADAM15 expression. Functional enrichment analyses indicated that apoptosis, cell adhesion was enriched. ADAM15 knockdown promoted apoptosis and suppressed proliferation, migration and invasion of liver cancer cells. The findings of western blot showed that ADAM15 knockdown reduced the expression of Bcl-2, Vimentin, N-Cadherin and Snail, and elevated the expression of Bax, E-cadherin and ZO-1. However, overexpression of ADAM15 had the opposite results. Collectively, our findings demonstrated that ADAM15 was connected with poor prognosis of HCC patients, and could be considered as a potential biomarker for the diagnosis and treatment of HCC.

The role of ADAM17 during liver damage.

A disintegrin and metalloprotease (ADAM) 17 is a membrane bound protease, involved in the cleavage and thus regulation of various membrane proteins, which are critical during liver injury. Among ADAM17 substrates are tumor necrosis factor α (TNFα), tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), the epidermal growth factor receptor (EGFR) ligands amphiregulin (AR) and heparin-binding-EGF-like growth factor (HB-EGF), the interleukin-6 receptor (IL-6R) and the receptor for a hepatocyte growth factor (HGF), c-Met. TNFα and its binding receptors can promote liver injury by inducing apoptosis and necroptosis in liver cells. Consistently, hepatocyte specific deletion of ADAM17 resulted in increased liver cell damage following CD95 stimulation. IL-6 trans-signaling is critical for liver regeneration and can alleviate liver damage. EGFR ligands can prevent liver damage and deletion of amphiregulin and HB-EGF can result in increased hepatocyte death and reduced proliferation. All of which indicates that ADAM17 has a central role in liver injury and recovery from it. Furthermore, inactive rhomboid proteins (iRhom) are involved in the trafficking and maturation of ADAM17 and have been linked to liver damage. Taken together, ADAM17 can contribute in a complex way to liver damage and injury.

Role of ADAM10 and ADAM17 in Regulating CD137 Function.

Human CD137 (4-1BB), a member of the TNF receptor family, and its ligand CD137L (4-1BBL), are expressed on immune cells and tumor cells. CD137/CD137L interaction mediates bidirectional cellular responses of potential relevance in inflammatory diseases, autoimmunity and oncology. A soluble form of CD137 exists, elevated levels of which have been reported in patients with rheumatoid arthritis and various malignancies. Soluble CD137 (sCD137) is considered to represent a splice variant of CD137. In this report, however, evidence is presented that A Disintegrin and Metalloproteinase (ADAM)10 and potentially also ADAM17 are centrally involved in its generation. Release of sCD137 by transfected cell lines and primary T cells was uniformly inhibitable by ADAM10 inhibition. The shedding function of ADAM10 can be blocked through inhibition of its interaction with surface exposed phosphatidylserine (PS), and this effectively inhibited sCD137 generation. The phospholipid scramblase Anoctamin-6 (ANO6) traffics PS to the outer membrane and thus modifies ADAM10 function. Overexpression of ANO6 increased stimulated shedding, and hyperactive ANO6 led to maximal constitutive shedding of CD137. sCD137 was functionally active and augmented T cell proliferation. Our findings shed new light on the regulation of CD137/CD137L immune responses with potential impact on immunotherapeutic approaches targeting CD137.

Strategies to Target ADAM17 in Disease: From its Discovery to the iRhom Revolution.

For decades, disintegrin and metalloproteinase 17 (ADAM17) has been the object of deep investigation. Since its discovery as the tumor necrosis factor convertase, it has been considered a major drug target, especially in the context of inflammatory diseases and cancer. Nevertheless, the development of drugs targeting ADAM17 has been harder than expected. This has generally been due to its multifunctionality, with over 80 different transmembrane proteins other than tumor necrosis factor α (TNF) being released by ADAM17, and its structural similarity to other metalloproteinases. This review provides an overview of the different roles of ADAM17 in disease and the effects of its ablation in a number of in vivo models of pathological conditions. Furthermore, here, we comprehensively encompass the approaches that have been developed to accomplish ADAM17 selective inhibition, from the newest non-zinc-binding ADAM17 synthetic inhibitors to the exploitation of iRhom2 to specifically target ADAM17 in immune cells.

\u03b1-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer\u2019s disease

BackgroundThe disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of APP. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset AD, though clear clinical-genetic correlates remain elusive.MethodsClinical-genetic and biomarker study of a first family with early- and late-onset AD associated with a nonsense ADAM10 mutation (p.Tyr167*). CSF analysis included AD core biomarkers, as well as Western blot of ADAM10 species and sAPPα and sAPPβ peptides. We evaluate variant’s pathogenicity, pattern of segregation, and further screened for the p.Tyr167* mutation in 197 familial AD cases from the same cohort, 200 controls from the same background, and 274 AD cases from an independent Spanish cohort.ResultsThe mutation was absent from public databases and segregated with the disease. CSF Aβ42, total tau, and phosphorylated tau of affected siblings were consistent with AD. The predicted haploinsufficiency effect of the nonsense mutation was supported by (a) ADAM10 isoforms in CSF decreased around 50% and (b) 70% reduction of CSF sAPPα peptide, both compared to controls, while sAPPβ levels remained unchanged. Interestingly, sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPPα and sAPPβ levels resembled those of controls. Therefore, a decreased sAPPα/sAPPβ ratio was an exclusive feature of mutant ADAM10 siblings. The p.Tyr167* mutation was not found in any of the other AD cases or controls screened.ConclusionsThis family illustrates the role of ADAM10 in the amyloidogenic process and the clinical development of the disease. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model for sporadic late-onset AD due to age-related downregulation of α-secretase. This report encourages future research on ADAM10 enhancers.

Functional Characterization of Colon-Cancer-Associated Variants in ADAM17 Affecting the Catalytic Domain.

Although extensively investigated, cancer is still one of the most devastating and lethal diseases in the modern world. Among different types, colorectal cancer (CRC) is most prevalent and mortal, making it an important subject of research. The metalloprotease ADAM17 has been implicated in the development of CRC due to its involvement in signaling pathways related to inflammation and cell proliferation. ADAM17 is capable of releasing membrane-bound proteins from the cell surface in a process called shedding. A deficiency of ADAM17 activity has been previously shown to have protective effects against CRC in mice, while an upregulation of ADAM17 activity is suspected to facilitate tumor development. In this study, we characterize ADAM17 variants found in tissue samples of cancer patients in overexpression studies. We here focus on point mutations identified within the catalytic domain of ADAM17 and could show a functional dysregulation of the CRC-associated variants. Since the catalytic domain of ADAM17 is the only region structurally determined by crystallography, we study the effect of each point mutation not only to learn more about the role of ADAM17 in cancer, but also to investigate the structure–function relationships of the metalloprotease.

The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner.

Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its regulatory adapter molecule iRhom2 for bacterial uptake by phagocytes. Inhibition of metalloproteinase activity led to increased phagocytosis of pHrodo labelled Gram-negative and -positive bacteria (E. coli and S. aureus, respectively) by human and murine monocytic cell lines or primary phagocytes. Bone marrow-derived macrophages showed enhanced uptake of heat-inactivated and living E. coli when they lacked either ADAM17 or iRhom2 but not upon ADAM10-deficiency. In monocytic THP-1 cells, corresponding short hairpin RNA (shRNA)-mediated knockdown confirmed that ADAM17, but not ADAM10, promoted phagocytosis of E. coli. The augmented bacterial uptake occurred in a cell autonomous manner and was accompanied by increased release of the chemokine CXCL8, less TNFα release and only minimal changes in the surface expression of the receptors TNFR1, TLR6 and CD36. Inhibition experiments indicated that the enhanced bacterial phagocytosis after ADAM17 knockdown was partially dependent on TNFα-activity but not on CXCL8. This novel role of ADAM17 in bacterial uptake needs to be considered in the development of ADAM17 inhibitors as therapeutics.

Abstract 282: Role of a Disintegrin and Metalloproteinase 15 in Cardiac Hypertrophy and Fibrosis Following Pressure Overload

Introduction: Disintegrin and metalloproteinases (ADAMs) are membrane-bound cell surface enzymes that are capable of both proteolytic functions (via the metalloproteinase domain) and adhesive functions (via the disintegrin domain), whereby they can influence cell function and extracellular matrix (ECM) remodelling in the heart. ADAM15 is unique among the ADAMs, as it is also capable of degrading ECM proteins. ADAM12 and ADAM17 have been reported to regulate cardiac hypertrophy, but the role of ADAM15 in cardiac hypertrophy is not known. This study investigates the role of ADAM15 in cardiac hypertrophy and fibrosis following pressure overload. Methods & Results: Genetically modified male ADAM15-deficient ( Adam15 -/- ) and wildtype (WT) mice were subjected to cardiac pressure overload by transverse aortic constriction (TAC). Cardiac function and structural remodelling were assessed using echocardiography at 2-, and 6-wks post-TAC. Hearts were excised at 2-, or 6-wks post-TAC. Adam15 -/- hearts presented greater hypertrophy and decreased cardiac systolic function at 6wks post-TAC, but no difference at 2wks post-TAC compared to WT-TAC mice. Adam15 -/- hearts also showed exacerbated fibrosis at 6wks post-TAC, but not at 2wks post-TAC, compared to WT. Mechanical strain (i.e. pressure overload) triggers two temporally activated pathways leading to an initial compensatory hypertrophy, which can culminate to decompensation and dilated cardiomyopathy. Consistent with the greater hypertrophy, phosphorylation of ERK1/2, JNK1/2/3, and GSK3β was increased in Adam15 -/- mice. The calcineurin-NFAT pathways can mediate pressure overload-induced hypertrophy, but we found that Adam15-deficiency did not impact this pathway. The mechanism responsible for this function of ADAM15 requires further investigation. Conclusion: This study reports a novel cardioprotective function for ADAM15 in pressure overload, where loss of ADAM15 promotes cardiac fibrosis and decompensated cardiac hypertrophy but does not alter the compensated hypertrophic response.

Macrolets: Outsized Extracellular Vesicles Released from Lipopolysaccharide-Stimulated Macrophages that Trap and Kill Escherichia coli.

SummaryMacrophages release a variety of extracellular vesicles (EVs). Here we describe a previously unreported class of EVs that are released from macrophages in response to Escherichia coli endotoxin, lipopolysaccharide (LPS), that we have named "macrolets" since they are extruded as large "droplets" released from macrophages. Morphologically, macrolets are anuclear, bounded by a single lipid membrane and structurally dependent on an actin cytoskeleton. Macrolets are enriched in tetraspanins and separable on this basis from their parent macrophages. Macrolets are distinguished from classic exosomes by their larger size (10–30 μm), discoid shape, and the presence of organelles. Macrolets are rich in both interleukin 6 (IL-6) and interleukin 6 receptor (IL-6R),and are capable of trapping and killing E. coli in association with production of reactive oxygen species. Our observations offer insights into the mechanisms by which macrophage activities may be amplified in sites of infection, inflammation, and healing.

Role of ADAM10 as a CD30 Sheddase in Classical Hodgkin Lymphoma.

Cancer cells generally recruit and influence non-malignant immune cells to support the tumor growth. Classical Hodgkin lymphoma (cHL) is a good example because the affected lymphoid tissue contains only a few malignant Hodgkin and Reed-Sternberg (H-RS) cells, which are supported by a massive infiltrate of lymphocytes, fibroblasts, and innate immune cells. The transmembrane receptor CD30, which is selectively expressed on the H-RS cells, plays an important role, not only in cell stimulation and intercellular communication but also in tumor diagnosis and targeted tumor therapy. Different protein processing pathways influence its functionality. Depending on the conditions, the receptor is internalized or released. The release of CD30 occurs either as an intact molecule, embedded in the membrane of extracellular vesicles (EVs), or as a cleaved soluble ectodomain (sCD30). CD30 cleavage is predominantly catalyzed by ADAM10. The enzyme is catalytically active in cells as well as in EVs and gradually releases sCD30. Because the circulation contains no CD30+ donor cells, this mechanism explains that the cleaved ectodomain represents the predominant form of CD30 in the plasma of cHL patients. CD30 processing might influence the impact of CD30 antibody-drug conjugates, such as Brentuximab Vedotin (BV). Whereas, ADAM10-degraded CD30 impedes the BV efficacy, tumor-derived EVs load bystander cells with CD30 and generate new targets among supporter cells. This crossfire effect might contribute to the enormous clinical impact of BV, whereas the ADAM10-dependent cleavage to the mild systemic off-target effects of the treatment with BV.

Adipocyte ADAM17 plays a limited role in metabolic inflammation

ABSTRACT The role of ADAM17, its substrates, and its natural inhibitor has been well studied in the context of inflammation, including metabolic inflammation, with mixed results. Previous studies examining global Adam17 knockdown models and ADAM17 inhibition using overexpression of endogenous ADAM17 inhibitors have shown improved metabolic health and decreased metabolic inflammation. However, there have been no studies examining the role of adipocyte ADAM17 using in vivo models. In this study, we developed an adipocyte-specific Adam17 knockout model using Adipoq-Cre-expressing mice crossed with Adam17-floxed mice. Using this model, we show that loss of adipocyte ADAM17 plays no evident role in baseline metabolic responses. Surprisingly, in a state of metabolic stress using high-fat diet (HFD), we observed that adipocyte ADAM17 had little effect overall on the metabolic phenotype as well as inflammatory cell populations. Using whole-body metabolic phenotyping, we show that loss of ADAM17 has no effect on energy utilization both at a baseline state as well as following HFD. However, lastly, using high-parameter flow cytometry, we show that loss of adipocyte ADAM17 alters macrophage and eosinophil populations following HFD. Overall, the studies presented here give more insight into the role of ADAM17 in metabolic responses and metabolic inflammation, specifically in adipocytes.

B cell ADAM17 controls T cell independent humoral immune responses through regulation of TACI and CD138

ADAM17 is known to contribute to the immune system through its shedding of tumor necrosis factor alpha (TNFα). However, the role of ADAM17 in B cell biology is not well characterized. To determine whether B cell ADAM17 contributes to T cell-independent humoral immune responses, we crossed CD19 Cre transgenic mice with mice bearing a floxed allele of ADAM17 (ADAM17CD19). In this study, we show a B cell intrinsic role for ADAM17 in regulating marginal zone B cell (MZB) numbers in mice. Interestingly, we demonstrate that the loss of B cell ADAM17 results in reduced MZB numbers in the naïve state and after immunization with T-independent antigen, yet enhanced humoral immunity to T cell independent antigens. We additionally find elevated TACI and CD138 levels on plasma cells following immunization in ADAM17CD19 mice. Overall, these findings suggest that B cell ADAM17 may orchestrate T independent immune responses through both MZB numbers and plasma cell antibody production.