Role of Human-Specific, Microglial Receptor Siglec-11 for Neuroinflammatory Diseases

Harald Neumann, M.D.

University of Bonn Medical Center

Funded in December, 2006: $100000 for 1 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . SELECTED PUBLICATIONS .

LAY SUMMARY

back to top

Is a Specific Receptor on Immune Cells in the Brain Involved in Degenerative Brain Diseases?

Investigators will study a “humanized” mouse model to determine whether a specific receptor on immune microglial cells in the brain blocks inflammatory responses, and whether malfunction of this receptor enables the inflammation that occurs in degenerative brain diseases.

The brain has been considered an “immune privileged” site becaue only immune microglial cells reside in the brain, and the blood-brain-barrier blocks all other immune cells from entering unless the brain is attacked by viruses or other foreign agents. This arrangement helps to shield brain cells from collateral damage that otherwise might occur from immune actions in the brain.  Brain cell axons and dendrities transmit and receive electrical signals, respectively.  They are particularly prone to immune-initiated inflammation, due to their high energy requirements, peculiar shapes, and a limited capacity for regeneration.  The researchers hypothesize that a receptor (called Siglec-11) located on microglial cells ordinarily sends signals that prevent inflammation from being initiated in the brain.  They further hypothesize that when the Siglec-11 receptor malfunctions in the presence of degenerative diseases, such as Alzheimer’s disease and multiple sclerosis, microglial cells are activated and secrete substances called cytokines that direct other immune cells to the sites of brain inflammation.

They will explore these hypotheses in a “humanized” mouse model, containing human Siglec-11 receptors on microglial cells.  They will analyze the receptor’s responses when challenged with EAE (experimental autoimmune encephalomyelitis).  EAE is the animal model disease of human multiple sclerosis (MS), a degenerative disease produced when immune cells mistake brain and spinal cord cells as foreign.  They will study the interaction between microglial cells and brain cells, especially the brain cells’ axons, and at synapses where axons pass signals on to dendrities of neighboring brain cells to communicate.

Significance:  If this research demonstrates that a malfunctioning receptor on immune microglial cells in the brain is involved in degenerative MS, the findings will identify a promising new therapeutic target for this autoimmune disease, and possibly for other degenerative brain diseases. 

ABSTRACT

back to top

Role of Human-Specific, Microglial Receptor Siglec-11 for Neuroinflammatory Diseases

Sialic acid-binding immunoglobulin superfamily lectins (Siglecs) are members of the immunoglobulin superfamily that bind to sialic acid. Siglec-11 is a recently identified human-specific CD33-related Siglec expressed on microglia, the brain resident macrophages. Siglec-11 activates src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2.

The function of Siglec-11 in microglial cells will be analyzed to determine its role in neuroinflammatory diseases. As an in vitro model, cultured human microglia and murine microglial cells genetically modified to overexpress human Siglec-11 will be examined. Microglial percursors will be obtained from murine and human embryonic stem cells to study Siglec-11 signaling. Gene transcripts and protein expression of cytokines and chemokines produced by microglia will be investigated after stimulation of Siglec-11. Furthermore, a microglial reporter cell line will be generated, which will be co-transduced with lentiviral vectors expressing human Siglec-11 tagged with citrine and SHP-1 tagged with cerulean. Lifetime-based fluorescence resonance energy transfer (FRET) analysis will be applied to this reporter cell line to study the interaction between Siglec-11 and SHP-1 and identify possible ligands stimulating Siglec-11 on the microglia. Particularly, we will analyze whether polysialic acids of neural cell adhesion molecules (PSA-NCAM) expressed on embryonic or electrically active neurons stimulate Siglec-11 of microglia.

To establish an in vivo model, transgenic mice expressing human Siglec-11 in microglia will be generated by lentivirally transduced embryonic stem cells expressing Siglec-11 under the microglial promoter Iba1. Transgenic mice will be challenged to experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. The effect of microglial Siglec-11 on the disease course and the inflammation will be studied.

Data obtained from this project will elucidate the role of Siglec-11 in microglial cells and its impact on the development of novel therapies for inflammatory and degenerative diseases of the central nervous system (CNS).

INVESTIGATOR BIOGRAPHIES

back to top
Harald Neumann, M.D.

• 1991: M.D. University of Wuerzburg, Germany.
• 1992-2001: Postdoctoral fellow and group leader at the Max-Planck-Institute of Psychiatry/ Neurobiology, Germany.
• 2001- 2004: Group leader at the European Neuroscience Institute Goettingen, Germany.
• 2004 - present:  Associate Professor at the Institute of Reconstructive Neurobiology, University Bonn, Germany.

Major objectives of our lab's research are to understand the involvement of microglial immunoreceptors in neurodegeneration and the role of innate immunity in neuroprotection and regeneration. Furthermore, adult and embryonic stem cell derived microglial precursor cells will be applied as tool for cell and gene therapy of neuroinflammatory and neurodegenerative diseases.

SELECTED PUBLICATIONS

back to top

Schwarting S., Litwak S., Hao W., Bähr M., Weise J., and Neumann H.  Hematopoietic stem cells reduce postischemic inflammation and ameliorate ischemic brain injury. Stroke. 2008 Jul 24.

Neumann H., Kotter M.R., and Franklin R.J.  Debris clearance by microglia: an essential link between degeneration and regeneration.  Brain. 2008 Jun 20.

Klotz L., Diehl L., Dani I., Neumann H., von Oppen N., Dolf A., Endl E., Klockgether T., Engelhardt B., and Knolle P.  Brain endothelial PPARγ controls inflammation-induced CD4+ T cell adhesion and transmigration in vitro.  J Neuroimmunol. 2007 Oct;190(1-2):34-43.

Fischer Y.H., Miletic H., Giroglou T., Litwak S., Stenzel W., Neumann H., and von Laer D.  A retroviral packaging cell line for pseudotype vectors based on glioma-infiltrating progenitor cells.  J Gene Med. 2007 May;9(5):335-44.

Takahashi K., Prinz M., Stagi M., Chechneva O., and Neumann H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate repair in an animal model of multiple sclerosis. PLoS Med. 2007 Apr;4(4):e124

Miletic H., Fischer Y., Litwak S., Giroglou T., Waerzeggers Y., Winkeler S., Li H., Himmelreich U., Stenzel W., Deckert M., Lange C., Neumann H., Jacobs AH., and von Laer D.   Bystander killing of malignant glioma by bone marrow-derived tumor-infiltrating progenitor cells expressing a suicide gene.   Mol Ther. 2007 Jul;15(7):1373-81.