Changes in Cellular Localization of Inter-Alpha Inhibitor Proteins after Cerebral Ischemia in the Near-Term Ovine Fetus

Inter-alpha Inhibitor Proteins (IAIPs) are key immunomodulatory molecules. Endogenous IAIPs are present in human, rodent, and sheep brains, and are variably localized to the cytoplasm and nuclei at multiple developmental stages. We have previously reported that ischemia-reperfusion (I/R) reduces IAIP concentrations in the fetal sheep brain. In this study, we examined the effect of I/R on total, cytoplasmic, and nuclear expression of IAIPs in neurons (NeuN⁺), microglia (Iba1⁺), oligodendrocytes (Olig2⁺) and proliferating cells (Ki67⁺), and their co-localization with histones and the endoplasmic reticulum in fetal brain cells. At 128 days of gestation, fetal sheep were exposed to Sham (n = 6) or I/R induced by cerebral ischemia for 30 min with reperfusion for 7 days (n = 5). Although I/R did not change the total number of IAIP⁺ cells in the cerebral cortex or white matter, cells with IAIP⁺ cytoplasm decreased, whereas cells with IAIP⁺ nuclei increased in the cortex. I/R reduced total neuronal number but did not change the IAIP⁺ neuronal number. The proportion of cytoplasmic IAIP⁺ neurons was reduced, but there was no change in the number of nuclear IAIP⁺ neurons. I/R increased the number of microglia and decreased the total numbers of IAIP⁺ microglia and nuclear IAIP⁺ microglia, but not the number of cytoplasmic IAIP⁺ microglia. I/R was associated with reduced numbers of oligodendrocytes and increased proliferating cells, without changes in the subcellular IAIP localization. IAIPs co-localized with the endoplasmic reticulum and histones. In conclusion, I/R alters the subcellular localization of IAIPs in cortical neurons and microglia but not in oligodendrocytes or proliferating cells. Taken together with the known neuroprotective effects of exogenous IAIPs, we speculate that endogenous IAIPs may play a role during recovery from I/R.