Title: Transport of the pro-inflammatory chemokines CCL2 (MCP-1) and CCL5 (RANTES) across the intact mouse blood-brain barrier is inhibited by heparin and eprodisate and increased with systemic inflammation.

Ozone (O3) is an air pollutant which primarily damages the lungs, but growing evidence supports that O3 exposure can also affect the brain. Serum amyloid A (SAA) and kynurenine have been identified as circulating factors that are upregulated by O3, and both can contribute to depressive-like behaviors in mice. However, little is known about the relations of O3 exposure to sickness and depressive-like behaviors in experimental settings. In this study, we evaluated O3 dose-, time- and sex-dependent changes in circulating SAA in context of pulmonary inflammation and damage, sickness and depressive-like behavioral changes, and systemic changes in kynurenine and indoleamine 2,3-dioxygenase (IDO), an enzyme that regulates kynurenine production and contributes to inflammation-induced depressive-like behaviors. Our results in Balb/c and CD-1 mice showed that 3ppm O3, but not 2 or 1ppm O3, caused elevations in serum SAA and pulmonary neutrophils, and these responses resolved by 48 hours. Sickness and depressive-like behaviors were observed at all O3 doses (1-3ppm), although the detection of certain behavioral changes varied by dose. We also found that Ido1 mRNA expression was increased in the brain and spleen 24 hours after 3ppm O3, and that kynurenine was increased in blood. Together, these findings indicate that acute O3 exposure induces transient symptoms of sickness and depressive-like behaviors which may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. We also present evidence that the IDO/kynurenine pathway is upregulated systemically following an acute exposure to O3 in mice.