Hepatic acute phase response protects the brain from focal inflammation during postnatal window of susceptibility.

Perinatal inflammation is known to contribute to neurodevelopmental diseases. Animal models of perinatal inflammation have revealed that the inflammatory response within the brain is age dependent, but the regulators of this variation remain unclear. In the adult, the peripheral acute phase response (APR) is known to be pivotal in the downstream recruitment of leukocytes to the injured brain. The relationship between perinatal brain injury and the APR has not been established. Here, we generated focal inflammation in the brain using interleukin (IL)-1ß at postnatal day (P)7, P14, P21 and P56 and studied both the central nervous system (CNS) and hepatic inflammatory responses at 4 h. We found that there is a significant window of susceptibility in mice at P14, when compared to mice at P7, P21 and P56. This was reflected in increased neutrophil recruitment to the CNS, as well as an increase in blood-brain barrier permeability. To investigate phenomena underlying this window of susceptibility, we performed a dose response of IL-1ß. Whilst induction of endogenous IL-1ß or intercellular adhesion molecule (ICAM)-1 in the brain and induction of a hepatic APR were dose dependent, the recruitment of neutrophils and associated blood-brain barrier breakdown was inversely proportional. Furthermore, in contrast to adult animals, an additional peripheral challenge (intravenous IL-1ß) reduced the degree of CNS inflammation, rather than exacerbating it. Together these results suggest a unique window of susceptibility to CNS injury, meaning that suppressing systemic inflammation after brain injury may exacerbate the damage caused, in an age-dependent manner.

Virus Infections on Prion Diseased Mice Exacerbate Inflammatory Microglial Response.

We investigated possible interaction between an arbovirus infection and the ME7 induced mice prion disease. C57BL/6, females, 6-week-old, were submitted to a bilateral intrahippocampal injection of ME7 prion strain (ME7) or normal brain homogenate (NBH). After injections, animals were organized into two groups: NBH (n = 26) and ME7 (n = 29). At 15th week after injections (wpi), animals were challenged intranasally with a suspension of Piry arbovirus 0.001% or with NBH. Behavioral changes in ME7 animals appeared in burrowing activity at 14 wpi. Hyperactivity on open field test, errors on rod bridge, and time reduction in inverted screen were detected at 15th, 19th, and 20th wpi respectively. Burrowing was more sensitive to earlier hippocampus dysfunction. However, Piry-infection did not significantly affect the already ongoing burrowing decline in the ME7-treated mice. After behavioral tests, brains were processed for IBA1, protease-resistant form of PrP, and Piry virus antigens. Although virus infection in isolation did not change the number of microglia in CA1, virus infection in prion diseased mice (at 17th wpi) induced changes in number and morphology of microglia in a laminar-dependent way. We suggest that virus infection exacerbates microglial inflammatory response to a greater degree in prion-infected mice, and this is not necessarily correlated with hippocampal-dependent behavioral deficits.