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Recently, the SARS-CoV-2 induced disease COVID-19 has spread all over the world. Nearly 20% of the patients have severe or critical conditions. SARS-CoV-2 exploits ACE2 for host cell entry. ACE2 plays an essential role in the renin–angiotensin–aldosterone system (RAAS), which regulates blood pressure and fluid balance. ACE2 also protects organs from inflammatory injuries and regulates intestinal functions. ACE2 can be shed by two proteases, ADAM17 and TMPRSS2. TMPRSS2-cleaved ACE2 allows SARS-CoV-2 cell entry, whereas ADAM17-cleaved ACE2 offers protection to organs. SARS-CoV-2 infection-caused ACE2 dysfunction worsens COVID-19 and could initiate multi-organ failure. Here, we will explain the role of ACE2 in the pathogenesis of severe and critical conditions of COVID-19 and discuss auspicious strategies for controlling the disease.

ADAM17, a prominent member of the ‘Disintegrin and Metalloproteinase’ (ADAM) family, controls vital cellular functions through cleavage of transmembrane substrates. Here we present evidence that surface exposure of phosphatidylserine (PS) is pivotal for ADAM17 to exert sheddase activity. PS exposure is tightly coupled to substrate shedding provoked by diverse ADAM17 activators. PS dependency is demonstrated in the following: (a) in Raji cells undergoing apoptosis; (b) in mutant PSA-3 cells with manipulatable PS content; and (c) in Scott syndrome lymphocytes genetically defunct in their capacity to externalize PS in response to intracellular Ca 2+ elevation. Soluble phosphorylserine but not phosphorylcholine inhibits substrate cleavage. The isolated membrane proximal domain (MPD) of ADAM17 binds to PS but not to phosphatidylcholine liposomes. A cationic PS-binding motif is identified in this domain, replacement of which abrogates liposome-binding and renders the protease incapable of cleaving its substrates in cells. We speculate that surface-exposed PS directs the protease to its targets where it then executes its shedding function. ADAM17 is a member of the ‘Disintegrin and Metalloproteinase’ family of proteases, that cleaves transmembrane substrates from the surfaces of cells. Here the authors show that surface exposure of phosphatidylserine is required for ADAM17 sheddase activity, possibly by directing the protease to its substrates.

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.

Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalization. Despite the global health burden of pancreatitis, currently, there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumor necrosis factor α (TNFα) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signaling. However, the role of ADAM17 in pancreatitis is unclear. To address this, Adam17 ex/ex mice—which are homozygous for the hypomorphic Adam17 ex allele resulting in marked reduction in ADAM17 expression—and their wild-type (WT) littermates were exposed to the cerulein-induced acute pancreatitis model, and acute (1-wk) and chronic (20-wk) pancreatitis models induced by the cigarette smoke carcinogen nicotine-derived nitrosamine ketone (NNK). Our data reveal that ADAM17 expression was up-regulated in pancreatic tissues of animal models of pancreatitis. Moreover, the genetic (Adam17 ex/ex mice) and therapeutic (ADAM17 prodomain inhibitor [A17pro]) targeting of ADAM17 ameliorated experimental pancreatitis, which was associated with a reduction in the IL-6 trans-signaling/STAT3 axis. This led to reduced inflammatory cell infiltration, including T cells and neutrophils, as well as necrosis and fibrosis in the pancreas. Furthermore, up-regulation of the ADAM17/IL-6 trans-signaling/STAT3 axis was a feature of pancreatitis patients. Collectively, our findings indicate that the ADAM17 protease plays a pivotal role in the pathogenesis of pancreatitis, which could pave the way for devising novel therapeutic options to be deployed against this disease.

The zinc containing matrix metalloproteinase enzyme regulates a diverse array of biological processes in health and disease, including ADAM17 (a disintegrin and metalloproteinase domain 17) enzyme. Due to its large substrate profile, ADAM17 is known to regulate diverse pathways of inflammation and adaptive immunity. However, the role of ADAM17 in modulating the pathogenesis of type 2 allergic asthma is largely unknown. To determine the in vivo contribution of ADAM17 in house dust mite (HDM)-induced airway inflammation and adaptive immune response, we assessed the deletion of ADAM17 in mice conventional dendritic cells (ΔDC) and employed a complementary chemical biology approach using small-molecule novel ADAM17 inhibitor (2155-17). DC-specific ADAM17 ablation (ΔDC) suppressed type 2/ eosinophilic polarized HDM allergic responses and is protected from developing AHR. DC isolated from ΔDC mice showed a reduced state of metabolic activity, immune priming function and suppressed allergen-specific type 2 cell polarizations. Intranasal administration of 2155-17 protected WT mice against type2/ eosinophilic polarized HDM allergic responses. These concurrent results from two independent approaches identify a novel role for ADAM17 as an upstream site in airway inflammation. Furthermore, targeting ADAM17 with a selective small-molecule inhibitor might be harnessed as a potential drug target for type 2-high allergic asthma.

Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease characterised by excessive deposition of extracellular matrix (ECM), resulting in high mortality rates. In this study, we provide evidence that ADAM17/PTGS2 plays a crucial role in inducing ferroptosis in fibroblasts, promoting PF. Initially, an assessment was made of ADAM17 protein levels in patients diagnosed with connective tissue diseases–interstitial lung diseases (CTD‐ILD), using ELISA assays. Confirmation of the relationship between ADAM17 and fibrosis was achieved by stimulating cells with PMA or TAPI‐1 (the ADAM17 inhibitor), in conjunction with the fibrosis‐inducing factor, TGFβ1. To further explore the major downstream proteins of ADAM17 contributing to altered PF, we employed mRNA transcriptomics. To further investigate the role of ADAM17/PTGS2 in promoting ferroptosis and fibrosis, we employed western blot assays, immunofluorescence and transmission electron microscopy (TEM). Furthermore, the effects of the ADAM17/PTGS2/ferroptosis pathway in PF were verified using Adeno‐associated virus (AAV)‐mediated ADAM17 gene knockdown in mice. In CTD‐ILD patients, ADAM17 expression was significantly elevated. Upon PMA stimulation, lung fibroblasts exhibited increased fibrosis‐related proteins, and the combined stimulation of PMA and TGFβ1 synergistically promoted cellular fibrosis. Conversely, TAPI‐1 alleviated fibrotic stimulation induced by TGFβ1. Transcriptomic analysis of lung fibroblast specimens overexpressing ADAM17 revealed significantly elevated PTGS2 expression levels. Knockdown and ferroptosis inhibition assays demonstrated that ADAM17 regulates ferroptosis in lung fibroblasts via PTGS2, ultimately inducing fibrosis. Furthermore, the deficiency of ADAM17 alleviated bleomycin‐induced PF and inflammation in mice. These findings first verified that ADAM17/PTGS2/ferroptosis is a novel mechanism for regulating PF; it provides a new theoretical basis for further exploring the treatment of PF.

Obesity is associated with a chronic state of low-grade inflammation and progressive tissue infiltration by immune cells and increased expression of inflammatory cytokines. It is established that interleukin 6 (IL6) regulates multiple aspects of metabolism, including glucose disposal, lipolysis, oxidative metabolism, and energy expenditure. IL6 is secreted by many tissues, but the role of individual cell types is unclear. We tested the role of specific cells using a mouse model with conditional expression of the Il6 gene. We found that IL6 derived from adipocytes increased, while IL6 derived from myeloid cells and muscle suppressed, macrophage infiltration of adipose tissue. These opposite actions were associated with a switch of IL6 signaling from a canonical mode (myeloid cells) to a noncanonical trans-signaling mode (adipocytes and muscle) with increased expression of the ADAM10/17 metalloprotease that promotes transsignaling by the soluble IL6 receptor α. Collectively, these data demonstrate that the source of IL6 production plays a major role in the physiological regulation of metabolism.

The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.

Oncogenic KRAS mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC. In genetically engineered and xenograft (human cell line and patient‐derived) Kras G12D ‐driven LAC models, the specific blockade of ADAM17, including with a non‐toxic prodomain inhibitor, suppressed tumor burden by reducing cellular proliferation. The pro‐tumorigenic activity of ADAM17 was dependent upon its threonine phosphorylation by p38 MAPK, along with the preferential shedding of the ADAM17 substrate, IL‐6R, to release soluble IL‐6R that drives IL‐6 trans‐signaling via the ERK1/2 MAPK pathway. The requirement for ADAM17 in Kras G12D ‐driven LAC was independent of bone marrow‐derived immune cells. Furthermore, in KRAS mutant human LAC, there was a significant positive correlation between augmented phospho‐ADAM17 levels, observed primarily in epithelial rather than immune cells, and activation of ERK and p38 MAPK pathways. Collectively, these findings identify ADAM17 as a druggable target for oncogenic KRAS ‐driven LAC and provide the rationale to employ ADAM17‐based therapeutic strategies for targeting KRAS mutant cancers. Synopsis Oncogenic KRAS mutations are associated with one‐third of lung adenocarcinoma (LAC) cases, yet the downstream molecular events that facilitate KRAS‐mediated tumorigenesis in the lung remain unresolved. This study reveals an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC. The specific genetic and therapeutic targeting of ADAM17, the latter with a non‐toxic prodomain inhibitor, suppressed tumour burden by reducing cellular proliferation in genetically‐engineered and xenograft mutant KRAS‐driven LAC models. The pro‐tumorigenic activity of ADAM17 in LAC was dependent upon its threonine phosphorylation by p38 MAPK. ADAM17 preferentially shed the substrate, IL‐6R, during LAC to release soluble IL‐6R that drives IL‐6 trans‐signaling via the ERK1/2 MAPK pathway. The requirement for ADAM17 in mutant KRAS‐driven LAC was independent of bone marrow‐derived hematopoietic immune cells. In KRAS mutant human LAC, augmented phospho‐ADAM17 levels were observed primarily in epithelial rather than immune cells, and significantly and positively correlated with activated p38 and ERK1/2 MAPK pathways. Graphical Abstract Oncogenic KRAS mutations are associated with one‐third of lung adenocarcinoma (LAC) cases, yet the downstream molecular events that facilitate KRAS‐mediated tumorigenesis in the lung remain unresolved. This study reveals an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC.

Alveolar macrophages (AMs) are specialized phagocytes in the airways that play a crucial role in maintaining bronchoalveolar homeostasis through phagocytosis, the clearance of apoptotic cells. However, the characteristics and molecular mechanisms of AMs-mediated phagocytosis during the pathogenesis of asthma remain poorly characterized. An ovalbumin (OVA)-induced asthma model was established in mice through intraperitoneal sensitization followed by intranasal challenge. AMs were isolated from the bronchoalveolar lavage fluid of control and OVA-induced mice using adherence-based purification. The phagocytic capacity of AMs, as well as the expression levels of CD36 and ADAM17, were quantified by flow cytometry. A significant reduction in both phagocytic efficiency and CD36 expression was found in the AMs of OVA-induced mice compared to control mice. Blockade of CD36 resulted in a marked decline in the phagocytic efficiency of normal AMs. Expression of ADAM17 was found to be notably elevated on the surface of AMs from OVA-induced mice compared to controls. Knockdown of ADAM17 led to a substantial increase in CD36 expression and a corresponding increase in phagocytic efficiency. Stimulation with tumor necrosis factor-α (TNF-α) resulted in a significant upregulation in ADAM17 and marked downregulation in CD36 expression levels, as well as impaired the phagocytic efficiency of AMs. Importantly, ADAM17 knockdown attenuated the TNF-α-mediated downregulation of CD36 expression and the associated impairment of phagocytic capacity in AMs. AMs from OVA-induced mice displayed significantly impaired phagocytic capacity. Airway TNF-α upregulated ADAM17, which in turn downregulated CD36 expression on AMs, ultimately suppressing their phagocytic function.