Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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A more recent version of this article appeared on December 1, 2005

Published online before print October 4, 2005
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0405222

Received for publication April 24, 2005.
Revised August 26, 2005.
Accepted for publication September 9, 2005.

Article

Are chemokines the third major system in the brain?

Martin W. Adler *{dagger}@ and Thomas J. Rogers *{dagger}{ddagger}

*Center for Substance Abuse Research, {ddagger}Fels Institute for Cancer Research and Molecular Biology, {dagger}Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania

@ To whom correspondence should be addressed. E-mail: baldeagl{at}temple.edu.


  Abstract

Chemokines are a family of small proteins involved in cellular migration and intercellular communication. Although the chemokines and their receptors are located throughout the brain, they are not distributed uniformly. Among the chemokines and their receptors that are arrayed disproportionately in glia and neurons are monocyte chemotactic protein-1/CC chemokine ligand 2 (CCL2), stromal cell-derived factor-1/CXC chemokine ligand 12 (CXCL12), fractalkine/CX3C chemokine ligand 1, interferon-{gamma}-inducible-protein-10/CXCL10, macrophage inflammatory protein-1{alpha}/CCL3, and regulated on activation, normal T cell expressed and secreted/CCL5. In the brain, they are found in the hypothalamus, nucleus accumbens, limbic system, hippocampus, thalamus, cortex, and cerebellum. The uneven distribution suggests that there may be functional roles for the chemokine "system," comprised of chemokine ligands and their receptors. In addition to anatomical, immunohistochemical, and in vitro studies establishing the expression of the chemokine ligands and receptors, there is an increasing body of research, which indicates that the chemokine system plays a crucial role in brain development and function. Our data indicate that the chemokine system can alter the actions of neuronally active pharmacological agents including the opioids and cannabinoids. Combined with evidence that the chemokine system in the brain interacts with neurotransmitter systems, we propose the following hypothesis: The endogenous chemokine system in the brain acts in concert with the neurotransmitter and neuropeptide systems to govern brain function. The chemokine system can thus be thought of as the third major transmitter system in the brain.

Key Words: opioids • heterologous desensitization • neuromodulators • interneuronal communication




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