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Cecile and Seymour Alpert Professor in Pain Research
Our lab is interested in:
Activation of receptor mediated phagocytosis of degenerated myelin in microglia and macrophages: complement receptor-3, scavenger receptor-AI/II, Galectin-3 and Syk.
The role of cytoskeleton (e.g. F-actin, myosin, Rac, Rho/ROCK and MLCK) in phagocytosis by microglia and macrophages.
The regulation of myelin phagocytosis by immune inhibitory receptor SIRPa and CD47 in microglia and macrophages.
The regulation of Wallerian degeneration, regeneration and functional recovery by immune inhibitory receptor SIRPa and CD47.
Gitik M, Elberg G, Reichert F, Tal M, Rotshenker S: Deletion of CD47 from Schwann cells and macrophages hastens myelin disruption/dismantling and scavenging in Schwann cells and augments myelin debris phagocytosis in macrophages. Journal of Neuroinflammation 2023
This study reveals two novel normally occurring CD47-dependent mechanisms that impede myelin debris clearance. First, CD47 expressed on Schwann cells inhibits myelin disruption/dismantling and debris scavenging in Schwann cells. Second, CD47 expressed on macrophages inhibits myelin debris phagocytosis in phagocytes. The two add to a third mechanism that we previously documented whereby CD47 on myelin ligates SIRPα on macrophages and microglia, triggering SIRPα-dependent phagocytosis inhibition in phagocytes. Thus, CD47 plays multiple inhibitory roles that combined impede myelin debris clearance, leading to delayed recovery from PNI. Similar inhibitory roles in microglia may hinder recovery from other pathologies in which repair depends on efficient phagocytosis (e.g., SCI and MS).
Rotshenker S: Galectin-3 (MAC-2) controls phagocytosis and macropinocytosis through intracellular and extracellular mechanisms. Front. Cell. Neurosci. 2022
A review article.
Elberg G, Liraz-Zaltsman S, Reichert F, Matozaki T, Tal M, Rotshenker S: Deletion of SIRPα (signal regulatory protein-α) promotes phagocytic clearance of myelin debris in Wallerian degeneration, axon regeneration, and recovery from nerve injury. Journal of Neuroinflammation 2019, 16: 277
Our findings suggest an intrinsic normally occurring SIRPα-dependent mechanism that impedes the in vivo removal of myelin debris in Wallerian degeneration by inhibiting the phagocytosis of myelin debris in macrophages, hence preventing fast growing axons from fully implementing their regenerative potential. Thus, accelerating the removal of myelin debris by eliminating SIRPα-dependent inhibition of phagocytosis will most likely advance recovery of functions from nerve injury.
Reichert F, Rotshenker S: Galectin-3 (MAC-2) Controls Microglia Phenotype Whether Amoeboid and Phagocytic or Branched and Non-phagocytic by Regulating the Cytoskeleton. Front Cell Neurosci 2019, 13: 90
Our aims in this project have been to further understand and validate the role of Galectin-3 as a key regulator of myelin-debris phagocytosis. First, we infected cultured primary microglia with Galectin-3 small-hairpin RNA (Gal-3-shRNA) to reduce/knockdown (KD) Galectin-3 protein levels, generating Gal-3-KD microglia. Second, we aimed to determine whether NCL and NPM activate phagocytosis as predicted from their ability to advance K-Ras signaling as Galectin-3 does. Third, we aimed to reveal which cytoskeletal molecules regulated by Galectin-3 activate phagocytosis. Our current findings suggest that Galectin-3 controls both microglia morphology and phagocytosis by targeting the cytoskeleton.
Rotshenker S: Chapter 39 – Traumatic Injury to Peripheral Nerves. In Nerves and Nerve Injuries. Edited by Tubbs RS, Rizk E, Shoja MM, Loukas M, Barbaro N, Spinner RJ. San Diego: Academic Press; 2015:611-628
Gitik M, Kleinhaus R, Hadas S, Reichert F, Rotshenker S: Phagocytic receptors activate and immune inhibitory receptor SIRPalpha inhibits phagocytosis through paxillin and cofilin. Front Cell Neurosci 2014, 8: 104
We tested whether SIRPα inhibits phagocytosis by regulating cytoskeleton function through paxillin and cofilin since (a) the cytoskeleton generates the mechanical forces that drive phagocytosis and (b) both paxillin and cofilin control cytoskeleton function. Paxillin and cofilin were transiently activated in microglia as phagocytosis was activated. In contrast, paxillin and cofilin were continuously activated and phagocytosis augmented in microglia in which SIRPα expression was knocked-down by SIRPα-shRNA. Further, levels of phagocytosis, paxillin activation, and cofilin activation positively correlated with one another. Taken together, these observations suggest a novel mechanism whereby paxillin and cofilin are targeted to control phagocytosis by both the activating signaling that phagocytic receptors produce by promoting the activation of paxillin and cofilin and the inhibiting signaling that immune inhibitory SIRPα produces by promoting the inactivation of paxillin and cofilin.
Rotshenker S: Wallerian degeneration: the innate-immune response to traumatic nerve injury. J Neuroinflammation 2011, 8: 109
Traumatic injury to peripheral nerves results in the loss of neural functions. Recovery by regeneration depends on the cellular and molecular events of Wallerian degeneration that injury induces distal to the lesion site, the domain through which severed axons regenerate back to their target tissues. Innate-immunity is central to Wallerian degeneration since innate-immune cells, functions and molecules that are produced by immune and non-immune cells are involved. The innate-immune response helps to turn the peripheral nerve tissue into an environment that supports regeneration by removing inhibitory myelin and by upregulating neurotrophic properties. The characteristics of an efficient innate-immune response are rapid onset and conclusion, and the orchestrated interplay between Schwann cells, fibroblasts, macrophages, endothelial cells, and molecules they produce. Wallerian degeneration serves as a prelude for successful repair when these requirements are met. In contrast, functional recovery is poor when injury fails to produce the efficient innate-immune response of Wallerian degeneration.
Gitik M, Liraz Zaltsman S, Oldenborg PA, Reichert F, Rotshenker S: Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPalpha (signal regulatory protein-alpha) on phagocytes. Journal of Neuroinflammation 2011, 8: 24
Traumatic injury to axons produces breakdown of axons and myelin at the site of the lesion and then further distal to this where Wallerian degeneration develops. The rapid removal of degenerated myelin by phagocytosis is advantageous for repair since molecules in myelin impede regeneration of severed axons. Thus, revealing mechanisms that regulate myelin phagocytosis by macrophages and microglia is important. We hypothesize that myelin regulates its own phagocytosis by simultaneous activation and down-regulation of microglial and macrophage responses. Activation follows myelin binding to receptors that mediate its phagocytosis (e.g. complement receptor-3), which has been previously studied. Down-regulation, which we test here, follows binding of myelin CD47 to the immune inhibitory receptor SIRPα (signal regulatory protein-α) on macrophages and microglia.
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Research fields:
Past – Synaptic transmission, plasticity and synapse formation
Present – Injury/regeneration and neurodegenerative diseases with special focus on the role of the immune system
Education and Academic positions:
1963 – 1970 Medicine, Hebrew University Faculty of Medicine, Jerusalem, Israel
1967 – MSc, Neurophysiology – Faculty prize for excellent MSc research project
1971 – MD – Faculty prize for excellent MD research thesis
1974 – 1977 Research Fellow, Dept of Neurobiology, Harvard University Medical School, Boston, Mass, USA
1978 – Present Hebrew University Faculty of Medicine, Jerusalem, Israel
1985 – 1986 and summers of 1988 and 1989, Visiting Professor, Dept. of Neurobiology, Stanford University Medical School, CA, USA
1998 – 1999 Visiting Professor, University of Miami – The Miami Project, FL, USA
2013 Visiting Professor, Kobe University, Japan
Administrative/Academic International/National/University/Faculty Appointments:
2014 – 2017 Director, Brain Disease Research Center (BDRC)
2009 – 2013 Member of the Israel Council for Higher Education evaluation committee in the field of Biology – Life sciences in Israel
2007 – 2011 Scientific Advisory Committee of ERA-Net NEURON (Networking the European Research Area – Europe’s neural network)
2007 – 2008 President, Israel Society for Neuroscience (ISFN)
2003 – 2004 Chairman, Israel National Council for the care and use of laboratory animals
2001 – 2005 Chairman, Hebrew University committee for teaching regulation
2002 – 2005 Hebrew University committees for academic appointments and promotions
1995 – 1997 Hebrew University board of managers, executive committee, and committee for academic policy
2006 – 2009 Vice Dean, Academic appointments & promotion and Academic Evaluation
1996 – 2000 Chairman, Faculty of Medicine teaching committee – division for studies in all BSc and MSc teaching programs
1995 – 1996 Chairman, Faculty of Medicine committee for planning and development
1994 – 1995 Chairman, Faculty of Medicine committee for establishing a new teaching program for a BSc degree in “Basic Medical Studies”
1992 – 1996 Chairman, Faculty of Medicine committee for the admission of medical students
Teaching:
1979 – 2010 In charge and lecturer of the course “Human Neurobiology and Neuroanatomy” given to students of Medicine, Dental Medicine, Basic Medical Sciences, and Neurobiology (MSc and PhD)
2011 – present Teaching in the course: “The nervous system of the healthy person”given to students of Medicine and Dental Medicine
2004 – Present Member of the International Brain Organization (IBRO) Lecture Visiting Team for teaching Neuroscience in developing countries