Brain Advance Access published online on September 12, 2008
Brain, doi:10.1093/brain/awn217
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Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation
1Department of Neurology and Neurosurgery, Washington University School of Medicine, St Louis, MO 63110, USA, 2Bioxell SpA, Milan 20132, Italy, 3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA, 4Department of Neurological Sciences, ‘Dino Ferrari’ Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan 20122, Italy and 5Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO 63110, USA
Correspondence to:
Laura Piccio, MD, PhD, Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S. Euclid Avenue, St Louis MO 63110, USA E-mail: picciol{at}neuro.wustl.edu
Triggering receptor expressed on myeloid cells 2 (TREM-2) is a membrane-bound receptor expressed by microglia and macrophages. Engagement of TREM-2 on these cells has been reported to reduce inflammatory responses and, in microglial cells, to promote phagocytosis. TREM-2 function is critical within the CNS, as its genetic deficiency in humans causes neurodegeneration with myelin and axonal loss. Blockade of TREM-2 worsened the mouse model for multiple sclerosis. In the present study, a soluble form of TREM-2 protein has been identified by immunoprecipitation and by ELISA. Soluble TREM-2 protein (sTREM-2) was detected in human CSF, and was compared among subjects with relapsing-remitting multiple sclerosis (RR-MS; n = 52), primary progressive multiple sclerosis (PP-MS; n = 21), other inflammatory neurologic diseases (OIND; n = 19), and non-inflammatory neurologic diseases (NIND; n = 41). Compared to NIND subjects, CSF sTREM-2 levels were significantly higher in RR-MS (P = 0.004 by ANOVA) and PP-MS (P < 0.001) subjects, as well as in OIND (P < 0.001) subjects. In contrast, levels of sTREM-2 in blood did not differ among the groups. Furthermore, TREM-2 was detected on a subset of CSF monocytes by flow cytometry, and was also highly expressed on myelin-laden macrophages in eight active demyelinating lesions from four autopsied multiple sclerosis subjects. The elevated levels of sTREM-2 in CSF of multiple sclerosis patients may inhibit the anti-inflammatory function of the membrane-bound receptor suggesting sTREM-2 to be a possible target for future therapies.
Key Words: multiple sclerosis; neuroinflammation; microglia; macrophages; immune regulation
Abbreviations: DC, dendritic cells; EAE, experimental autoimmune encephalomyelitis; EDSS, Expanded Disability Status Score; MSSS, multiple sclerosis severity score; NHD, Nasu–Hakola Disease; NIND, non-inflammatory neurological disease; OIND, other inflammatory neurological disease; PP-MS, primary progressive multiple sclerosis; RR-MS, relapsing remitting multiple sclerosis; sTREM-2, soluble TREM-2; TREM-2, triggering receptor expressed on myeloid cells-2
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Received March 17, 2008. Revised July 14, 2008. Accepted August 13, 2008.
*Present address: University of Alabama at Birmingham School of Medicine, 440 Sparks center, 1720, 7th Avenue, South Birmingham, AL 35233-0017, USA.