Erythropoietin-mediated neuroprotection by cytokine receptor-like factor 3

• Applicant: Professor Ralf Heinrich, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398214842

• Final Report Year: 2022

Final Report Abstract

In summary, our experiments provided the following new information: Human CRLF3 is a receptor that activates anti-apoptotic intracellular pathways. - Human CRLF3 is a (the first identified) receptor for the non-erythropoietic but tissue-protective Epo splice variant EV-3. - Locust CRLF3 is activated by various Epo-like ligands that selectively mediate tissue-protection without stimulating erythropoiesis. - Like human CRLF3, locust CRLF3 is expressed in multiple tissues including nervous system, muscle and hemocytes. - Like human Epo, the endogenous CRLF3 ligand plays a dual role as circulating hormone and auto- /paracrine signal in the nervous system. - The circulating CRLF3 ligand in locust hemolymph is conserved across insects, allowing the activation of beetle CRLF3-mediated neuroprotection. - As previously reported for mammalian cells, acetylcholinesterase accumulates under apoptogenic conditions and its suppression or pharmacological inhibition prevents apoptotic cell death. - Activation of insect CRLF3 suppresses upregulation of pro-apoptotic acetylcholinesterase expression under apoptogenic conditions, identifying the regulation of acetylcholinesterase as one anti-apoptotic mechanism contributing to neuroprotection. With the recently reported function of CRLF3 in mammalian thrombopoiesis, CRLF3 was added to the list of molecularly related hematopoietic cytokine receptors (EpoR, TPO-R, GCSF-R) with additional cell-protective functions in other tissues. Of this cytokine receptor family, only CRLF3 is conserved across both vertebrates and invertebrates making CRLF3-signalling the likely evolutionary origin of vertebrate hematopoiesis-/cell protection-regulating cytokine receptors. Identifying the ancient CRLF3-ligand will contribute to clarify the evolution of cytokine/cytokine-receptor-signalling.

Publications

• Acetylcholinesterase promotes apoptosis in insect neurons. Apoptosis 25: 730-746, 2020
  Knorr D.Y., Georges N.S., Pauls S., Heinrich R.
  
• Locust hemolymph conveys erythropoietin-like cytoprotection via activation of the cytokine receptor CRLF3. Frontiers in Physiology 12: 648245, 2021
  Knorr D.Y., Hartung D., Schneider K., Hintz L., Pies H.S., Heinrich R.
  
• Anti-apoptotic and neuroprotective erythropoietin/CRLF3-signalling in insects and humans. 2022
  Debbra Yasemin Knorr