Ephrin-A1 and the sheddase ADAM12 are upregulated in COVID-19

Abstract

More than 3.5 million people have died globally from COVID-19, yet an effective therapy is not available. It is, therefore, important to understand the signaling pathways that mediate disease progression in order to identify new molecular targets for therapeutic development. Here, we report that the blood serum levels of ephrin-A1 and the sheddase ADAM12 were significantly elevated in COVID-19 patients treated at SUNY Downstate Hospital of Brooklyn, New York. Both ephrin-A1 and ADAM12 are known to be involved in inflammation and regulate endothelial cell permeability, thus providing a gateway to lung injury. The clinical outcome correlated with the ephrin-A1 and ADAM12 serum levels during the first week of hospitalization. In contrast, the serum levels of TNFα were elevated in only a small subset of the patients, and these same patients also had highly elevated levels of the sheddase ADAM17. These data indicate that ephrin-A1-mediated inflammatory signaling may contribute to COVID-19 disease progression more so than TNFα-mediated inflammatory signaling. They also support the notion that, in COVID-19 inflammation, ADAM12 sheds ephrin-A1, while ADAM17 sheds TNFα. Furthermore, the results suggest that elevated serum levels and activity of cytokines, such as TNFα, and other secreted inflammatory molecules, such as ephrin-A1, are not simply due to overexpression, but also to upregulation of sheddases that release them into the blood circulation. Our results identify ephrin-A1, ADAM12, and other molecules in the ephrin-A1 signaling pathway as potential pharmacological targets for treating COVID-19 inflammation.

Role of the extracellular matrix in COVID-19

“…The ADAM12 receptor and ephrin-A1, one of the ADAM12 substrates, play a role in inflammation and endothelial cell permeability. Among COVID-19 patients, some had significantly elevated concentrations of ADAM12 and ephrin-A1 in their blood serum, with critical patients having the highest levels[ 58 ]. Therefore, the inflammatory response mediated by Ephrin-A1 may be one of the major factors in the morbidity and mortality related to COVID-19.…”

Proteomics and Biochemical Analyses of Secreted Proteins Revealed a Novel Mechanism by Which ADAM12S Regulates the Migration of Gastric Cancer Cells

“…In summary, using the SPECS method, quantitative proteomics, and biochemical approaches, we discovered many ADAM12S-regulated downstream targets in the cultured medium of gastric cancer cells and elucidated a novel mechanism by which ADAM12S promotes the migration of gastric cancer cells. Previous and recent clinical experiments revealed that ADAM12 was highly expressed in the tissue, serum, and urine of cancer patients or other diseases, including COVID-19 patients . Therefore, the discovery of the biological function and the signaling pathways that ADAM12 is involved in may help us to assess the therapeutic value of this protein and its associated signaling pathways.…”

“…Previous and recent clinical experiments revealed that ADAM12 was highly expressed in the tissue, serum, and urine of cancer patients or other diseases, including COVID-19 patients. 53 Therefore, the discovery of the biological function and the signaling pathways that ADAM12 is involved in may help us to assess the therapeutic value of this protein and its associated signaling pathways.…”

The EPH/Ephrin System in Colorectal Cancer

“…In parallel, its impact in every step of carcinogenesis has been increasingly documented [ 1 , 12 , 13 ]. It has even been proposed as a potential treatment target for COVID-19 infection [ 14 ].…”