Neutralization of macrophage inflammatory protein 2 (MIP-2) and MIP-1 alpha attenuates neutrophil recruitment in the central nervous system during experimental bacterial meningitis

Chemokines are low-molecular-weight chemotactic cytokines that have been sh own to play a central role in the perivascular transmigration and accumulat ion of specific subsets of leukocytes at sites of tissue damage. Using in s itu hybridization (ISH), we investigated the mRNA induction of macrophage i nflammatory protein 2 (MIP-2), MIP-1 alpha, monocyte chemoattractant protei n 1 (MCP-1), and RANTES. Challenge of infant rats' brains with Haemwophilus influenzae type b intraperitoneally resulted in the time-dependent express ion of MIP-2, MIP-1 alpha, MCP-1, and RANTES, which was maximal 24 to 48 h postinoculation. Immunohistochemistry showed significant increases in neutr ophils and macrophages infiltrating the meninges, the ventricular system, a nd the periventricular area. The kinetics of MIP-2, MIP-1 alpha, 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-1 alp ha antibodies (Abs) resulted in significant reduction of neutrophils. Admin istration of anti-MCP-1 Abs significantly decreased macrophage infiltration . Combined studies of ISH and immunohistochemistry showed that MIP-2- and M IP-1 alpha positive cells were neutrophils and macrophages, MCP 1-positive cells were neutrophils, macrophages, and astrocytes, Expression of RANTES w as localized predominantly to resident astrocytes and microglia, The presen t study indicates that blacking of MIP-2 or MIP-1 alpha bioactivity in vivo results in decreased neutrophil influx, These data are also the first demo nstration that the C-C chemokine MIP-1 alpha is involved in neutrophil recr uitment in vive.