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Neutralization of macrophage inflammatory protein 2 (MIP-2) and MIP-1α attenuates neutrophil recruitment in the central nervous system during experimental bacterial meningitis
Division of Neurology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Division of Infectious Diseases, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Division of Neurology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Division of Neurology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
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1999 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 67, no 5, 2590-2601 p.Article in journal (Refereed) Published
Abstract [en]

Chemokines are low-molecular-weight chemotactic cytokines that have been shown to play a central role in the perivascular transmigration and accumulation of specific subsets of leukocytes at sites of tissue damage. Using in situ hybridization (ISH), we investigated the mRNA induction of macrophage inflammatory protein 2 (MIP-2), MIP-1α, monocyte chemoattractant protein 1 (MCP-1), and RANTES. Challenge of infant rats’ brains with Haemophilus influenzae type b intraperitoneally resulted in the time-dependent expression of MIP-2, MIP-1α, MCP-1, and RANTES, which was maximal 24 to 48 h postinoculation. Immunohistochemistry showed significant increases in neutrophils and macrophages infiltrating the meninges, the ventricular system, and the periventricular area. The kinetics of MIP-2, MIP-1α, MCP-1, and RANTES mRNA expression paralleled those of the recruitment of inflammatory cells and disease severity. Administration of anti-MIP-2 or anti-MIP-1α antibodies (Abs) resulted in significant reduction of neutrophils. Administration of anti-MCP-1 Abs significantly decreased macrophage infiltration. Combined studies of ISH and immunohistochemistry showed that MIP-2- and MIP-1α-positive cells were neutrophils and macrophages. MCP-1-positive cells were neutrophils, macrophages, and astrocytes. Expression of RANTES was localized predominantly to resident astrocytes and microglia. The present study indicates that blocking of MIP-2 or MIP-1α bioactivity in vivo results in decreased neutrophil influx. These data are also the first demonstration that the C-C chemokine MIP-1α is involved in neutrophil recruitment in vivo.

Place, publisher, year, edition, pages
1999. Vol. 67, no 5, 2590-2601 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-81946PubMedID: 10225925OAI: oai:DiVA.org:liu-81946DiVA: diva2:556755
Available from: 2012-09-26 Created: 2012-09-26 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Modulation of inflammatory mediators during experimental bacterial meningitis
Open this publication in new window or tab >>Modulation of inflammatory mediators during experimental bacterial meningitis
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bacterial meningitis is a worldwide health problem with high morbidity and mortality mainly caused by Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae. It is an inflammatory disease of the central nervous system (eNS) initiated by cell wall or membrane components from the bacteria. This stimulates an accumulation of polymorphonuclear leukocytes (PMN) in the subarachnoid space, where they are further stimulated by bacterial products or by cytokines to release inflammatory mediators including nitric oxide (NO) and chemokines. The role of these mediators in the inflammatory response in vivo is not fully understood. The aim of present thesis was to investigate the role of these inflammatory mediators using Haemophilus influenzae type b (Hib) in an experimental model for meningitis.

Intraperitoneal inoculation of Hib into infant rats resulted in induction of iNOS mRNA that was detected in brain sections 12 hr post-inoculation (p.i). The number of iNOS mRNA-containing cells was gradually reduced and normalized by day 7 p.i. The numbers of intracerebral iNOS expressing cells was also detected after 12h p.i., but they were further elevated to a peak at 72h p.i. The iNOS positive brain sections also bound antibody specific for nitrotyrosine.

Brains of infant rats challenged intraperitoneally with Hib resulted in a time-dependent expression of MIP-2, MIP-1α MCP-1 and RANTES, which were detected with maximum levels at 24-48 h p.i. There were significant increases in the number of neutrophils and macrophages in the meninges, the ventricular system and the periventricular area. The kinetics of MIP-2, MIP-α, MCP-1 and RANTES mRNA expression paralleled those of the recruitment of inflammatory cells and disease severity. Administration of anti-MIP-2 or anti-MIP-1α antibodies (Abs) reduced the number of infiltrated neutrophils, anti-MCP-1 Abs reducing macrophage infiltration.

Hib infection resulted in 100% mortality by 72 h p.i. and pretreatment with CNI-1493, a tetravalent guanylhydrazone, resulted in 75% survival. This treatment also reduced the number of infiltrating granulocytes in the brain and reduced the number of cells producing TNF-α and IL-Iß in the spleen.

Macrophages (RAW 246.7) preincubated with CNI-1493 prior to activation with LPS/IFN- γ had decreased NO production and reduced iNOS expression. The production of reactive oxygen species (ROS) was increased in FMLP-stimulated granulocytes following CNI-1493-treatment, whereas their F-actin content, motility and chemotaxis were decreased under the same condition.

Conclusion: During experimental Hib meningitis iNOS was upregulated and associated with NO production. The chemokines MIP-2, MIP-1α MCP and RANTES were expressed and shown to be involved in neutrophil recruitment in vivo. Blockade of MIP-2 or MIP-1α bioactivity in vivo resulted in decreased neutrophil influx. CNI-1493 treatment increased animal survival by attenuating CNS inflammation and in vitro CNI-1493 had a direct effect on both macrophages and PMN.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2005. 40 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 907
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-30081 (URN)15546 (Local ID)91-8529914-6 (ISBN)15546 (Archive number)15546 (OAI)
Public defence
2005-06-09, Eken, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-26Bibliographically approved

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