Perivascular macrophages lack cyclooxygenase-2 induction and do not mediate fever

Perivascular macrophages, immune cells located in the Virchow-Robin spaces that surround small arterioles, capillaries, and venules in the brain, have been suggested to produce prostaglandins upon immune stimulation and influence centrally elicited disease symptoms such as fever. Here, we examined in mice the role of perivascular macrophages in the febrile response. Using a mouse line carrying a loxP-flanked transcriptional blocker upstream of the Ptgs2 gene, crossed with a Cx3cr1-Cre line, we sought to selectively express the prostaglandin-synthesizing enzyme cyclooxygenase-2 in Cx3cr1-expressing cells, including most perivascular macrophages as well as brain microglial cells. Whereas immune challenge by intravenous injection of lipopolysaccharide resulted in a febrile response in WT mice, StopfloxPtgs2 Cx3cr1-CreERT2 mice instead displayed profound hypothermia, similar to mice with whole-body deletion of cyclooxygenase-2. Real-time PCR analysis showed no or negligible levels of Ptgs2 transcript in the StopfloxPtgs2 Cx3cr1-CreERT2 mice, and immunohistochemistry showed no cyclooxygenase-2 immunoreactivity in perivascular macrophages or reporter gene expression indicative of cyclooxygenase-2 transcription. We conclude that perivascular macrophages do not produce appreciable amounts of cyclooxygenase-2 upon immune challenge, at least not in the mouse, and therefore do not contribute to the febrile response.