Chorioamnionitis Induces a Unique Time Course of Inflammatory Changes and Immune Reponses in the Brain and Spleen.

Abstract

Inflammatory oxidative microenvironments can alter heme oxygenase-1 (HO-1) homeostasis. Dysregulation of HO-1 favors proinflammatory signals while transferrin receptor 1 (TfR1) regulates anti-inflammatory signal transduction. Previously, we have shown that chorioamnionitis (CHORIO) induces sustained elevations in HO-1/TfR1 at postnatal day (P)2 and mononuclear cell-driven inflammation at term age equivalent P7. Here, we hypothesized that an altered HO-1/TfR1 developmental time course would coincide with inflammatory/immune signal changes in the brain. We used realtime polymerase chain reaction (RT-PCR), multiplex electrochemiluminescent immunoassay (MECI), and flow cytometry (FC) to study changes in pro- and anti-inflammatory gene expression, immune cell secretome, and immune cells at critical and clinically relevant timepoints following CHORIO. We found an acute reduction in an anti-inflammatory signature in the cortex on embryonic day (E)19. This was followed by an increased pro-inflammatory signature on postnatal day (P)2. There were also significant alterations in the phenotypic distribution of splenic T cells on P7, a key organ in immune function. Furthermore, we showed that the microenvironment of the cortex at P21 was skewed towards a pro-inflammatory state by significant increases in IL-6. The prominence of T-helper cells (Th) in brain concomitant with a proinflammatory microenvironment at P21 suggests emerging inflammation and potential for neural injury. Defining how these and other inflammatory/immune signatures contribute to perinatal brain injury and investigating distinct immune signatures at more developmental time courses will be beneficial for targeting emerging therapies.