Abstract
In the present study, the authors evaluated the contributions of the CXC chemokine ligand (CXCL)10 to leukocyte recruitment into the central nervous system (CNS) and disease development. Instillation of a replication-deficient adenovirus that expresses CXCL10 (AdCXCL10) into the CNS of C57BL/6 mice resulted in a rapid (day 3) and prolonged (day 21) infiltration of both CD4+ and CD8+ T cells as compared to mice infected with an adenovirus vector containing β-galactosidase (Adβgal). Despite increased T-cell infiltration into the CNS of AdCXCL10-infected mice, production of proinflammatory chemokines normally associated with the recruitment of activated T cells into the CNS was muted and mice developed limited neuropathology. Therefore, these results indicate that T-cell infiltration in the absence of appropriate activation is not sufficient to induce pathology within the CNS and that additional signals other than CXCL10 are required for induction of an immune-mediated neurologic disease.
Keywords: chemokines, coronavirus, neuropathology, T cells
Footnotes
This work was supported by NIH grant NS/AG41249 awarded to TEL.
References
- Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM, Maheshwari S, Kleinman HK, Reaman GH, Tosato G. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med. 1995;182:155–162. doi: 10.1084/jem.182.1.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Asensio VC, Lassmann S, Pagenstecher A, Steffensen SC, Henriksen SJ, Campbell IL. C10 is a novel chemokine expressed in experimental inflammatory demyelinating disorders that promotes recruitment of macrophages to the central nervous system. Am J Pathol. 1999;154:1181–1189. doi: 10.1016/S0002-9440(10)65370-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Balashov KE, Rottman JB, Weiner HL, Hancock WW. CCR5+ and CXCR3+ T cells are increased in multiple sclersosis and their ligands MIP-1α and IP-10 are expressed in demyelinating brain lesions. Proc Natl Acad Sci U S A. 1999;96:6873–6878. doi: 10.1073/pnas.96.12.6873. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bell MD, Taub DD, Kunkel SJ, Strieter RM, Foley R, Gauldie J, Perry VH. Recombinant human adenovirus with Rat MIP-2 gene insertion causes prolonged PMN recruitment to the murine brain. Eur J Neurosci. 1996;8:1803–1811. doi: 10.1111/j.1460-9568.1996.tb01324.x. [DOI] [PubMed] [Google Scholar]
- Biddison WE, Cruikshank WW, Center DM, Pelfrey CM, Taub DD, Turner RV. CD8+ myelin peptide-specific T cells can chemoattract CD4+ myelin peptide-specific T cells: importance of IFN-inducible protein 10. J immunol. 1998;160:444–448. [PubMed] [Google Scholar]
- Bonecchi RG, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray A, Mantovani A, Sinigaglia F. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med. 1998;187:129–134. doi: 10.1084/jem.187.1.129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boztug K, Carson MJ, Pham-Mitchell N, Asensio VC, DeMartino J, Campbell IL. Leukocyte infiltration but not neurodegeneration in the CNS of transgenic mice with astrocyte production of the CXC chemokine ligand 10. J Immunol. 2002;169:1505–1515. doi: 10.4049/jimmunol.169.3.1505. [DOI] [PubMed] [Google Scholar]
- Charles PC, Chen X, Horwitz MS, Brosnan CF. Differential chemokine induction by the mouse adenovirus type-1 in the central nervous system of susceptible and resistant strains of mice. J NeuroVirol. 1999;5:55–64. doi: 10.3109/13550289909029746. [DOI] [PubMed] [Google Scholar]
- Chen BP, Kuziel WA, Lane TE. Lack of CCR2 results in increased mortality and impaired leukocyte activation and trafficking following infection of the central system with a neurotropic coronavirus. J Immunol. 2001;167:4585–4592. doi: 10.4049/jimmunol.167.8.4585. [DOI] [PubMed] [Google Scholar]
- Cole AM, Ganz T, Liese AM, Burdick MD, Liu L, Strieter RM. IFN-inducible ELR− CXC chemokines display defensin-like antimicrobial activity. J Immunol. 2001;167:623–627. doi: 10.4049/jimmunol.167.2.623. [DOI] [PubMed] [Google Scholar]
- Dufour JH, Dziejman M, Liu MT, Leung JH, Lane TE, Luster AD. IFN-γ-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J Immunol. 2002;168:3195–3204. doi: 10.4049/jimmunol.168.7.3195. [DOI] [PubMed] [Google Scholar]
- Farber JM. MIG and IP-10: CXC chemokines that target lymphocytes. J Leukoc Biol. 1997;61:246–257. [PubMed] [Google Scholar]
- Fife BT, Kennedy KJ, Paniagua MC, Lukacs NW, Kunkel SL, Luster AD, Karpus WJ. CXCL10 (IFN-γ-inducible protein-10) control of encephalitogenic CD4+ T cell accumulation in the central nervous system during experimental autoimmune encephalomyelitis. J Immunol. 2001;166:7617–7624. doi: 10.4049/jimmunol.166.12.7617. [DOI] [PubMed] [Google Scholar]
- Flier J, Boorsma DM, van Beek PJ, Nieboer C, Stoof TJ, Willemze R, Tensen CP. Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation. J Pathol. 2001;194:398–405. doi: 10.1002/1096-9896(200108)194:4<397::AID-PATH899>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
- Gattass CR, King LB, Luster AD, Ashwell JD. Constitutive expression of interferon gamma-inducible protein 10 in lymphoid organs and inducible expression in T cells and thymocytes. J Exp Med. 1994;179:1373–1378. doi: 10.1084/jem.179.4.1373. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gottlieb AB, Luster AD, Posnett DN, Carter DM. Detection of a gamma interferon-induced protein IP-10 in psoriatic plaques. J Exp Med. 1988;168:941–948. doi: 10.1084/jem.168.3.941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hancock WW, Gao W, Csizmadia V, Faia KL, Shemmeri N, Luster AD. Donor-derived IP-10 initiates development of acute allograft rejection. J Exp Med. 2001;193:975–980. doi: 10.1084/jem.193.8.975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hancock WW, Lu B, Gao W, Csizmadia V, Faia K, King JA, Smiley ST, Ling M, Gerard NP, Gerard C. Requirement of the chemokine receptor CXCR3 for acute allograft rejection. J Exp Med. 2000;192:1515–1519. doi: 10.1084/jem.192.10.1515. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Janatpour MJ, Hudak S, Sathe M, Sedgwick JD, McEvoy LM. Tumor necrosis factor-dependent segmental control of MIG expression by high endothelial venules in inflamed lymph nodes regulates monocytes recruitment. J Exp Med. 2001;193:1375–1384. doi: 10.1084/jem.194.9.1375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lahrtz F, Piali L, Nadal D, Pfister HW, Spanaus KS, Bagiolini M. Chemotactic activity on mononuclear cells in the cerebrospinal fluid of patients with viral meningitis is mediated by interferon-gamma inducible protein-10 and monocyte chemotactic protein-1. Eur J Immunol. 1997;27:2484–2489. doi: 10.1002/eji.1830271004. [DOI] [PubMed] [Google Scholar]
- Lane TE, Asensio VC, Yu N, Paoletti AD, Campbell IL, Buchmeier MJ. Dynamic regulation of α- and β-chemokine expression in the central nervous system during mouse hepatitis virus-induced demyelinating disease. J Immunol. 1998;160:970–978. [PubMed] [Google Scholar]
- Lane TE, Liu MT, Chen BP, Asensio VC, Samawi RM, Paoletti AD, Campbell IL, Kunkel SL, Fox HS, Buchmeier MJ. A central role for CD4+ T cells and RANTES in virus-induced central nervous system inflammation and demyelination. J Virol. 2000;74:1415–1424. doi: 10.1128/JVI.74.3.1415-1424.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu MT, Chen BP, Oertel P, Buchmeier MJ, Armstrong D, Hamilton TA, Lane TE. Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurologic function in a viral model of multiple sclerosis. J Immunol. 2000;165:2327–2330. [Google Scholar]
- Liu MT, Armstrong D, Hamilton TA, Lane TE. Expression of Mig (monokine induced by interferon-γ) is important in T lymphocyte recruitment and host defense following viral infection of the central nervous system. J Immunol. 2001;166:1790–1795. doi: 10.4049/jimmunol.166.3.1790. [DOI] [PubMed] [Google Scholar]
- Liu MT, Kierstead HS, Lane TE. Neutralization of the chemokine CXCL10 reduced inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis. J Immunol. 2001;167:4091–4097. doi: 10.4049/jimmunol.167.7.4091. [DOI] [PubMed] [Google Scholar]
- Luster AD, Ravetch JV. Biochemical characterization of a gamma interferon-inducible cytokine (IP-10) J Exp Med. 1987;166:1084–1097. doi: 10.1084/jem.166.4.1084. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pang L, Ye W, Che X, Rossler BJ, Betz AL, Yang G. Reduction of inflammatory response in the mouse brain with adenoviral-mediated transforming growth factor-β1 expression. Stroke. 2000;32:544–552. doi: 10.1161/01.str.32.2.544. [DOI] [PubMed] [Google Scholar]
- Patel DD, Zachariah JP, Whichard LP. CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. Clin Immunol. 2001;98:39–45. doi: 10.1006/clim.2000.4957. [DOI] [PubMed] [Google Scholar]
- Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest. 1998;101:746–754. doi: 10.1172/JCI1422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Romagnani P, Beltrame C, Annunziato F, Lasagni L, Luconi M, Galli G, Cosmi L, Maggi E, Salvadori M, Pupilli C, Serio M. Role for interactions between IP-10/Mig and CXCR3 in proliferative glomerulonephritis. J Am Soc Nephrol. 1999;10:2518–2526. doi: 10.1681/ASN.V10122518. [DOI] [PubMed] [Google Scholar]
- Shimada A, Morimoto J, Kodama K, Suzuki R, Oikawa Y, Funae O, Kasuga A, Saruta T, Narumi S. Elevated serum IP-10 levels observed in type 1 diabetes. Diabetes Care. 2001;24:510–515. doi: 10.2337/diacare.24.3.510. [DOI] [PubMed] [Google Scholar]
- Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN. Expression of the interferon-gamma-inducible chemokines IP-10 and Mig and their receptor, CXCR3, in multiple sclerosis lesions. Neuropathol Appl Neurobiol. 2000;26:133–142. doi: 10.1046/j.1365-2990.2000.026002133.x. [DOI] [PubMed] [Google Scholar]
- Sorensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, Qin S, Sellebjerg F, Strieter RM, Frederiksen JL, Ransohoff RM. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest. 1999;103:807–815. doi: 10.1172/JCI5150. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stalder AK, Carson MJ, Pagenstscher A, Asensio VC, Kincaid C, Benedict M, Powell HC, Masliah E, Campbell IL. Late-onset chronic inflammatory encephalopathy in immune-competent and severe combined immune-deficient (SCID) mice with astrocytetargeted expression of tumor necrosis factor. Am J Pathol. 1998;153:767–783. doi: 10.1016/S0002-9440(10)65620-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Strieter RM, Kunkel SL, Arenberg DA, Burdick MD, Polverini PJ. Interferon γ-inducible protein 10 (IP-10), a member of the C-X-C chemokine family, is an inhibitor of angiogenesis. Biochem Biophys Res Commun. 1995;210:51–57. doi: 10.1006/bbrc.1995.1626. [DOI] [PubMed] [Google Scholar]
- Stylianou E, Yndestad A, Sikkeland LI, Bjerkeli V, Damas JK, Haug T, Eiken HG, Aukrust P, FrOland SS. Effects on interferon-alpha on gene expression of chemokines and members of the tumour necrosis factor superfamily in HIV-infected patients. Clin Exp Immunol. 2002;130:279–285. doi: 10.1046/j.1365-2249.2002.01980.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tani M, Fuentes ME, Peterson JW, Trapp BD, Durham SK, Loy JK, Bravo R, Ransohoff RM, Lira SA. Neutrophil infiltration, glial reaction, and neurological disease in transgenic mice expressing the chemokine N51-KC in oligodendrocytes. J Clin Invest. 1996;98:529–539. doi: 10.1172/JCI118821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vanguri P, Farber JM. Identification of CRG-2. An interferon-inducible mRNA predicted to encode a murine monokine. J Biol Chem. 1990;265:15049–15057. [PubMed] [Google Scholar]
- Wang X, Li X, Schmidt DB, Foley JJ, Barone FC, Ames RS, Sarau HM. Identification and molecular characterization of rat CXCR3: receptor expression and interferon-inducible protein-10 binding are increased in focal stroke. Mol Pharmacol. 2000;57:1190–1198. [PubMed] [Google Scholar]
- Xia MQ, Bacskai BJ, Knowles RB, Qin SX, Hyman BT. Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer’s disease. J Neuroimmunol. 2000;108:227–235. doi: 10.1016/S0165-5728(00)00285-X. [DOI] [PubMed] [Google Scholar]