Rats and Mice Exhibit Distinct Inflammatory Reactions after Spinal Cord Injury JULIE M. SROGA, 1 T. BUCKY JONES, 2 KRISTINA A. KIGERL, 3 VIOLETA M. MCGAUGHY, 1 AND PHILLIP G. POPOVICH 1–3 * 1 Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210 2 The Neuroscience Graduate Studies Program, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210 3 Integrated Biomedical Science Graduate Program, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210 ABSTRACT Spinal contusion pathology in rats and mice is distinct. Cystic cavities form at the impact site in rats while a dense connective tissue matrix occupies the injury site in mice. Because inflammatory cells coordinate mechanisms of tissue injury and repair, we evaluated whether the unique anatomical presentation in spinally injured rats and mice is associated with a species-specific inflammatory response. Immunohistochemistry was used to compare the leukocytic infiltrate between rats and mice. Microglia/macrophage reactions were similar between species; however, the onset and magnitude of lymphocyte and dendritic cell (DC) infiltration were markedly different. In rats, T-cell numbers were highest between 3 and 7 days postinjury and declined by 50% over the next 3 weeks. In mice, significant T-cell entry was not evident until 14 days postinjury, with T-cell numbers doubling between 2 and 6 weeks. Dendritic cell influx paralleled T-cell infiltration in rats but was absent in mouse spinal cord. De novo expression of major histocompatability class II molecules was increased in both species but to a greater extent in mice. Unique to mice were cells that resembled lymphocytes but did not express lymphocyte-specific markers. These cells extended from blood vessels within the fibrotic tissue matrix and expressed fibronectin, collagen I, CD11b, CD34, CD13, and CD45. This phenotype is characteristic of fibrocytes, specialized blood- borne cells involved in wound healing and immunity. Thus, species-specific neuroinflamma- tion may contribute to the formation of distinct tissue environments at the site of spinal cord injury in mice and rats. J. Comp. Neurol. 462:223–240, 2003. © 2003 Wiley-Liss, Inc. Indexing terms: species differences; neuroinflammation; T-lymphocyte; macrophage; fibrocyte; wound repair; dendritic cell As interest in genetic approaches to manipulate the CNS has increased, so have attempts to develop mouse models of spinal cord injury (SCI; Zhang et al., 1998; Kuhn and Wrathall, 1998; Steward et al., 1999; Jakeman et al., 2000; Joshi and Fehlings, 2002a,b; Seitz et al., 2002; Seki et al., 2002). Indeed, transgenic and gene knockout mice have been used to study various mechanisms of delayed neuronal/glial cell death following traumatic SCI (Fa- rooque et al., 2001; Kim et al., 2001; Beattie et al., 2002; Jones et al., 2002; Noble et al., 2002; Pan et al., 2002). However, despite the convenience of genetic manipulation in mice, SCI lesion pathology in this species is distinct from that seen in other mammals. Namely, in rats, ham- sters, cats, monkeys, and humans, a rim of anatomically preserved white matter surrounds a fluid-filled cystic cav- ity at the site of spinal contusion/compression trauma (Bresnahan et al., 1976; Balentine, 1978; Blight, 1983; Noble and Wrathall, 1985; Blight and Decrescito, 1986; Bunge et al., 1993; Inman and Steward, 2003). In contrast, Grant sponsor: National Institutes of Health/National Institute for Neu- rological Disorders and Stroke; Grant number: NS37846; Grant sponsor: National Institutes of Health/National Institutes on Aging; Grant number: NIH-NINDS/NIA P50 DE13749. *Correspondence to: Phillip G. Popovich, Department of Molecular Vi- rology, Immunology and Medical Genetics, 2078 Graves Hall, 333 W. 10th Ave, Columbus, OH 43210. E-mail: popovich.2@osu.edu Received 18 December 2002; Revised 25 February 2003; Accepted 27 March 2003. DOI 10.1002/cne.10736 Published online the week of June 2, 2003 in Wiley InterScience (www. interscience.wiley.com). THE JOURNAL OF COMPARATIVE NEUROLOGY 462:223–240 (2003) © 2003 WILEY-LISS, INC.