Abstract
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)-1β 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-1β. Whilst induction of endogenous IL-1β 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-1β) 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.
Highlights
Neuroinflammation is implicated in the aetiology of neurodevelopmental disorders, such as autism, schizophrenia (Bayer et al, 1999; Bloomfield et al, 2016; Estes and McAllister, 2015; Fillman et al, 2013; Trépanier et al, 2016; Vargas et al, 2005) and cerebral palsy
Injection of 1 ng IL-1b increased blood–brain barrier permeability in the ipsilateral striatum at P14, but not at other ages evaluated, or in the contralateral striatum. These results indicate that injection of 1 ng IL-1b induced an acute window of susceptibility at P14 in mice, which was characterized by excessive recruitment of neutrophils to the injected striatum and increased blood–brain barrier permeability to endogenous IgG when compared to earlier and later stages of development
Our findings suggest that the suppression of the peripheral inflammatory response after perinatal brain injury might increase rather than decrease the central nervous system (CNS) inflammatory response and outcomes to injury
Summary
The impact of inflammation on development appears to be highly dependent on the timing of the challenge; for instance, autism and schizophrenia have been associated with infection during the first and second trimester, while vulnerability to cerebral palsy was highest in the last trimester and early postnatal period (Atladóttir et al, 2010; Brown et al, 2004; Dubowitz et al, 1985; Mednick et al, 1988).
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