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Chronic expression of monocyte chemoattractant protein-1 in the central nervous system causes delayed encephalopathy and impaired microglial function in mice

Deren Huang^*, Jerome Wujek^*,1, Graham Kidd^*, Toby T. He^*, Astrid Cardona^*, Margaret E. Sasse^*, Erica J. Stein^*, Jacqueline Kish^*, Marie Tani^*, Israel F. Charo, Amanda E. Proudfoot, Barrett J. Rollins, Tracy Handel^¶ and Richard M. Ransohoff^*,2

^* Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA;
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA;
Serono Pharmaceutical Research Institute, Geneva, Switzerland;
Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; and
^¶ University of California, Berkeley, California, USA

² Correspondence: Department of Neurosciences NC3, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA. E-mail: ransohr{at}ccf.org

Increased central nervous system (CNS) levels of monocyte chemoattractant protein 1 [CC chemokine ligand 2 (CCL2) in the systematic nomenclature] have been reported in chronic neurological diseases such as human immunodeficiency virus type 1-associated dementia, amyotrophic lateral sclerosis, and multiple sclerosis. However, a pathogenic role for CCL2 has not been confirmed, and there is no established model for the effects of chronic CCL2 expression on resident and recruited CNS cells. We report that aged (>6 months) transgenic (tg) mice expressing CCL2 under the control of the human glial fibrillary acidic protein promoter (huGFAP-CCL2_hi tg⁺ mice) manifested encephalopathy with mild perivascular leukocyte infiltration, impaired blood brain barrier function, and increased CD45-immunoreactive microglia, which had morphologic features of activation. huGFAP-CCL2_hi tg⁺ mice lacking CC chemokine receptor 2 (CCR2) were normal, showing that chemokine action via CCR2 was required. Studies of cortical slice preparations using video confocal microscopy showed that microglia in the CNS of huGFAP-CCL2_hi tg⁺ mice were defective in expressing amoeboid morphology. Treatment with mutant CCL2 peptides, a receptor antagonist and an obligate monomer, also suppressed morphological transformation in this assay, indicating a critical role for CCL2 in microglial activation and suggesting that chronic CCL2 exposure desensitized CCR2 on microglia, which in the CNS of huGFAP-CCL2_hi tg⁺ mice, did not up-regulate cell-surface expression of major histocompatibility complex class II, CD11b, CD11c, or CD40, in contrast to recruited perivascular macrophages that expressed enhanced levels of these markers. These results indicate that huGFAP-CCL2_hi tg⁺ mice provide a useful model to study how chronic CNS expression of CCL2 alters microglial function and CNS physiology.—Huang, D., Wujek, J., Kidd, G., He, T. T., Cardona, A., Sasse, M. E., Stein, E. J., Kish, J., Tani, M., Charo, I. F., Proudfoot, A. E., Rollins, B. J., Handel, T., Ransohoff, R. M. Chronic expression of monocyte chemoattractant protein-1 in the central nervous system causes delayed encephalopathy and impaired microglial function in mice.

Key Words: chemokines • chemokine receptors • transgenic mice • macrophages

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