Eosinophil-Derived Neurotoxin

Eosinophil-derived neurotoxin (EDN), also known as eosinophil protein-X or eosinophil-derived neurotoxin, is one of the four "major proteins" found in the large specific granules of human eosinophilic leukocytes. Eosinophil granulocytes are mobilized from the bone marrow into the blood and tissues in response to Th2 stimuli characteristic of allergic inflammation and parasitic helminth infections. Although EDN was defined as a neurotoxin after its discovery and initial characterization, it is also constitutively expressed in human liver tissue. Its expression can be induced in macrophages by proinflammatory stimuli. EDN is now known to have ribonuclease activity and is a member of the extensive RNase A superfamily. Versch. Investigations into the potential physiological functions of EDN have provided insights into its role in antiviral host defense, as a chemoattractant for human dendritic cells and, more recently, as an endogenous ligand for the Toll-like receptor (TLR). Of particular note are findings that EDN can initiate signal transduction via interaction with the pattern recognition receptor Toll-like receptor (TLR)-2.

It was shown that EDN is an enzymatically active ribonuclease capable of generating acid-soluble ribonucleotides from acid-insoluble polymeric substrate with an efficiency comparable to that of bovine pancreatic ribonuclease (RNase A).

Molecular cloning of EDN clearly defined its membership of the now recognized extensive RNase A superfamily. Completion of the human genome eventually led to the recognition of 13 human RNase A ribonuclease genes. Eight of the RNase A ribonuclease genes encode enzymatically active proteins, and five encode divergent, inactive variants that have lost crucial structural or catalytic elements. EDN is encoded by the RNASE2 gene .

EDN alone has little to no cytotoxicity to somatic cells, apart from neurotoxicity. However, when EDN is bound to a single-chain antibody against the transferrin receptor, it is internalized as a ribonucleolytically active cytoxin.

The role of eosinophils in response to respiratory virus infection, particularly respiratory syncytial virus (RSV) infection, is well known. Respiratory viruses (RSV, rhinovirus, adenovirus) are among the most important factors known to exacerbate asthma, a disease in which eosinophils play an important role in promoting pathogenesis. Although eosinophils are generally thought to contribute only negatively to inflammatory processes, there is evidence that eosinophils may also contribute positively to host antiviral defenses.

EDN as an endogenous ligand for TLR2: Evidence has been provided that EDN can act as an endogenous ligand for the Toll-like receptor (TLR) 2. On the basis of various studies Based on various studies, EDN was classified as an alarmin, which are mediators capable of activating antigen-presenting cells (e.g. dendritic cells) and thus represent a link between innate and acquired immune responses.

In the 1930s, as part of his search for an infectious etiology for Hodgkin's disease, M. H. Gordon described a neurotoxic syndrome caused by the intracerebral injection of a human lymph node suspension into rabbits. Ultimately, the infiltrating eosinophils proved to be the source of the neurotoxicity, and one of the two neurotoxic components was termed "eosinophil neurotoxin".

1. Kim CK (2023) Eosinophil-derived neurotoxin reference values in asthma: The way forward. Clin Exp Allergy 53:1141-1143.
2. Malinovschi A et al. (2023) Clinical Potential of Eosinophil-Derived Neurotoxin in Asthma Management. J Allergy Clin Immunol Pract 11:750-761.
3. Rosenberg HF (2008) Eosinophil-derived neurotoxin / RNase 2: connecting the past, the present and the future. Curr Pharm Biotechnol 9:135-140.