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Infection and Immunity, May 1999, p. 2590-2601, Vol. 67, No. 5
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Neutralization of Macrophage Inflammatory Protein 2 (MIP-2) and MIP-1alpha Attenuates Neutrophil Recruitment in the Central Nervous System during Experimental Bacterial Meningitis

Asim Diab,1,* Hana Abdalla,2 Hu Lun Li,1 Fu Dong Shi,1 Jie Zhu,1 Bo Höjberg,1 Lars Lindquist,2 Bengt Wretlind,3 Moiz Bakhiet,2 and Hans Link1

Divisions of Neurology,1 Infectious Diseases,2 and Clinical Bacteriology,3 Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden

Received 7 October 1998/Returned for modification 24 November 1998/Accepted 19 January 1999

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-1alpha , 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-1alpha , 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-1alpha , 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-1alpha 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-1alpha -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-1alpha bioactivity in vivo results in decreased neutrophil influx. These data are also the first demonstration that the C-C chemokine MIP-1alpha is involved in neutrophil recruitment in vivo.

* Corresponding author. Mailing address: Division of Neurology, Karolinska Institute, Huddinge University Hospital, S-141 68 Huddinge, Sweden. Phone: 46-8-58582277. Fax: 46-8-58587080. E-mail: Asim.Diab{at}cnsf.ki.se.

Infection and Immunity, May 1999, p. 2590-2601, Vol. 67, No. 5
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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