A Protective Role for ELR plus Chemokines during Acute Viral Encephalomyelitis

被引:48
作者
Hosking, Martin P. [1 ]
Liu, Liping [2 ]
Ransohoff, Richard M. [2 ]
Lane, Thomas E. [1 ,3 ]
机构
[1] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA
[2] Cleveland Clin, Dept Neurosci, Neuroinflammat Res Ctr, Cleveland, OH 44106 USA
[3] Univ Calif Irvine, Inst Immunol Infect Dis & Vaccines, Irvine, CA USA
基金
美国国家卫生研究院;
关键词
CENTRAL-NERVOUS-SYSTEM; MOUSE HEPATITIS-VIRUS; BLOOD-BRAIN-BARRIER; CD8(+) T-CELLS; MEDIATED HOST-DEFENSE; CXC CHEMOKINES; SPINAL-CORD; NEUTROPHIL RECRUITMENT; LEUKOCYTE INFILTRATION; RECEPTOR-2; LIGANDS;
D O I
10.1371/journal.ppat.1000648
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The functional role of ELR-positive CXC chemokines in host defense during acute viral-induced encephalomyelitis was determined. Inoculation of the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice resulted in the rapid mobilization of PMNs expressing the chemokine receptor CXCR2 into the blood. Migration of PMNs to the CNS coincided with increased expression of transcripts specific for the CXCR2 ELR-positive chemokine ligands CXCL1, CXCL2, and CXCL5 within the brain. Treatment of JHMV-infected mice with anti-CXCR2 blocking antibody reduced PMN trafficking into the CNS by >95%, dampened MMP-9 activity, and abrogated blood-brain-barrier (BBB) breakdown. Correspondingly, CXCR2 neutralization resulted in diminished infiltration of virus-specific T cells, an inability to control viral replication within the brain, and 100% mortality. Blocking CXCR2 signaling did not impair the generation of virus-specific T cells, indicating that CXCR2 is not required to tailor anti-JHMV T cell responses. Evaluation of mice in which CXCR2 is genetically silenced (CXCR2-/- mice) confirmed that PMNs neither expressed CXCR2 nor migrated in response to ligands CXCL1, CXCL2, or CXCL5 in an in vitro chemotaxis assay. Moreover, JHMV infection of CXCR2-/- mice resulted in an approximate 60% reduction of PMN migration into the CNS, yet these mice survived infection and controlled viral replication within the brain. Treatment of JHMV-infected CXCR2-/- mice with anti-CXCR2 antibody did not modulate PMN migration nor alter viral clearance or mortality, indicating the existence of compensatory mechanisms that facilitate sufficient migration of PMNs into the CNS in the absence of CXCR2. Collectively, these findings highlight a previously unappreciated role for ELR-positive chemokines in enhancing host defense during acute viral infections of the CNS.
引用
收藏
页数:14
相关论文
共 82 条
  • [1] Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis
    Agrawal, S
    Anderson, P
    Durbeej, M
    van Rooijen, N
    Ivars, F
    Opdenakker, G
    Sorokin, LM
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2006, 203 (04) : 1007 - 1019
  • [2] CXC chemokines generate age-related increases in neutrophil-mediated brain inflammation and blood-brain barrier breakdown
    Anthony, D
    Dempster, R
    Fearn, S
    Clements, J
    Wells, G
    Perry, VH
    Walker, K
    [J]. CURRENT BIOLOGY, 1998, 8 (16) : 923 - 926
  • [3] APPELBERG R, 1994, IMMUNOLOGY, V83, P302
  • [4] Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia
    Asahi, M
    Wang, XY
    Mori, T
    Sumii, T
    Jung, JC
    Moskowitz, MA
    Fini, ME
    Lo, EH
    [J]. JOURNAL OF NEUROSCIENCE, 2001, 21 (19) : 7724 - 7732
  • [5] CXCR2/CXCR2 ligand biology ischemia-reperfusion injury
    Belperio, JA
    Keane, MP
    Burdick, MD
    Gomperts, BN
    Xue, YY
    Hong, K
    Mestas, J
    Zisman, D
    Ardehali, A
    Saggar, R
    Lynch, JP
    Ross, DJ
    Strieter, RM
    [J]. JOURNAL OF IMMUNOLOGY, 2005, 175 (10) : 6931 - 6939
  • [6] Bergmann CC, 1999, J IMMUNOL, V163, P3379
  • [7] The JHM strain of mouse hepatitis virus induces a spike protein-specific D-b-restricted cytotoxic T cell response
    Bergmann, CC
    Yao, Q
    Lin, M
    Stohlman, SA
    [J]. JOURNAL OF GENERAL VIROLOGY, 1996, 77 : 315 - 325
  • [8] Rapid recruitment of neutrophils containing prestored IL-12 during microbial infection
    Bliss, SK
    Butcher, BA
    Denkers, EY
    [J]. JOURNAL OF IMMUNOLOGY, 2000, 165 (08) : 4515 - 4521
  • [9] NEUTROPHIL AND B-CELL EXPANSION IN MICE THAT LACK THE MURINE IL-8 RECEPTOR HOMOLOG
    CACALANO, G
    LEE, J
    KIKLY, K
    RYAN, AM
    PITTSMEEK, S
    HULTGREN, B
    WOOD, WI
    MOORE, MW
    [J]. SCIENCE, 1994, 265 (5172) : 682 - 684
  • [10] Ratio of local to systemic chemokine concentrations regulates neutrophil recruitment
    Call, DR
    Nemzek, JA
    Ebong, SJ
    Bolgos, GL
    Newcomb, DE
    Remick, DG
    [J]. AMERICAN JOURNAL OF PATHOLOGY, 2001, 158 (02) : 715 - 721