Medicine & Research

The Potential Role of Chemokines in Remyelination

By Kakuri M.Omari, Ph.D.

In the multiple sclerosis lesion, the oligodendrocyte (the myelin-producing cell) is selectively destroyed because of an abnormal immune response occurring within the central nervous system. The CNS is normally sequestered from the immune system. If immune cells do enter, they may detect proteins normally found in the CNS, but which are foreign to them and may mount an attack. Since oligodendrocytes are depleted from older (established) MS lesions, prospects for remyelination are poor and without myelin repair, return of lost function is unlikely. Therefore, strategies to help oligodendrocytes survive, increase in number, or repopulate lesion areas hold much promise.

Chemokines: Small Proteins Play a Big Role

A family of proteins, (produced by lymphocytes and blood vessels to attract immune cells into tissues) known as chemokines (chemoattractant cytokines), have been shown to be important mediators of inflammation and lymphocyte trafficking into the brain.

These small proteins have the ability to cause a number of cellular responses including:

gene expression (initiating protein production)

• chemotaxis (influencing migration of cells)

• cell polarization (organization of cell and organ architecture)

• adhesion (enabling cell attachment)

Chemokines produced by one cell interact with specific receptor molecules on other cells and such interactions have been proposed to play an important role in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). 

Since we now have access to technologies that render us able to influence a number of cellular responses by manipulating or inducing the production of chemokines and their receptors, we can investigate the different roles that chemokines may play, either in the initial stages or the reparative phase of MS. Existing evidence from work on rodents has demonstrated that one chemokine, known as CXCL1, induces the proliferation and inhibits the migration of cells destined to become oligodendrocytes. Moreover, when MS is present, recent findings from our laboratory have demonstrated for the first time the existence of several chemokine receptors on oligodendrocytes in the human CNS, and have shown that expression of their respective chemokines can be induced by stimulation with other proteins on astrocytes (the cells important in water and electrolyte balance, structural integrity and scarring in the CNS). Based on this information, we set out to test the hypothesis that certain chemokines produced by stimulated astrocytes regulate oligodendrocyte cell behavior (proliferation and migration), causing the two cell types to interact during the evolution of the MS lesion.

Investigating the Effects of Chemokines on Inflammation and Demyelination

To investigate the effects of chemokines during inflammation in the CNS, we generated a mouse model in which the chemokine, CXCL1 (a molecule normally produced by cells lining blood vessel walls), can be specifically turned on within the CNS under the control of an astrocyte-specific gene. In other words, by giving this so-called transgenic mouse a specific stimulus (an antibiotic in its diet), we can turn the chemokine gene on and wherever it is expressed (in this case, within astrocytes in the CNS), these cells will produce the protein.

For our experiments, transgenic and control mice were immunized with myelin proteins to induce EAE. After the animals began to display paralysis, chemokine production was turned on by administration of the antibiotic, doxycycline. Our results from the first set of experiments have shown that animals in which the chemokine was produced at higher levels display a much milder clinical course of the disease. Analysis of CNS tissue from these mice has revealed that although immune cells (inflammation) were present in the CNS of these transgenic mice and control animals during the early phases of the disease, demyelination and damage to nerve fibers were more prominent in the control mice. In other words, the chemokine had a protective effect in the transgenic mice. In the later phases of EAE, inflammation and demyelination were significantly diminished and nerve fiber damage was markedly less in chemokine-producing transgenic mice, as compared to controls.

Interestingly, relative to the levels of nerve damage, myelin repair was greater in the transgenic group, and there was an accompanying increase in oligodendrocytes, suggestive of a protective and/or proliferative effect on oligodendrocytes. Further analysis showed that far fewer T cells (lymphocytes) and macrophages (scavenger cells) were detected in the spinal cord of transgenic mice than in controls during the later phase of the disease. In addition to diminished inflammation and damage  in the transgenic mice, cell proliferation (indicated by the incorporation of a marker of cell division) was also evident in the white matter after turning on the chemokine. Ongoing efforts are designed to determine whether there is an increase in oligodendrocytes following overproduction of this chemokine, an event that might bode well for remyelination.

Chemokines May Lead To Novel Strategies in Remyelination

Our preliminary findings suggest a role for the chemokine CXCL1 in exerting a neuroprotective role in EAE. Based on previous studies in rodents by others showing that this chemokine induces division of oligodendrocyte precursor cells and halts their migration during development and repair, the current line of investigation may lead to novel strategies to enhance the remyelination of MS lesions and thus encourage the return of lost function.

Dr. Kakuri M. Omari is a neuro-immunologist at the Albert Einstein College of Medicine in NYC, in the Molecular Neuropathology laboratory of Dr. Cedric S. Raine. Trained in Canada, Dr. Omari obtained a B.Sc. in Biochemistry in 1995, and a Ph.D. in Pathology and Experimental Medicine at the University of British Columbia in 2001. Dr. Omari received the 2004 Whitaker Prize for MS Research from the Consortium of MS Centers (CMSC), and Best Poster Award at the 8th International Congress of Neuroimmunology for his current work on chemokines.

(Last reviewed 8/2009)