Exposure of foetal neural progenitor cells to IL‐1β impairs their proliferation and alters their differentiation – a role for maternal inflammation?

Abstract

J. Neurochem. (2012) 120, 964–973. Abstract During pregnancy, activation of the maternal immune system results in inflammation in the foetal nervous system. The causative agents are pro‐inflammatory cytokines like interleukin‐1β (IL‐1β), produced by the foetus. In this study, we examine the effect of IL‐1β on the proliferation and differentiation of neural progenitor cells (NPCs) to better understand its potential effects on the developing brain. We find that the IL‐1β receptor (IL‐1R1) is expressed in the ventral mesencephalon of the developing brain. Furthermore, IL‐1R1 is expressed on Nestin‐positive, Sox‐2‐positive NPCs. IL‐1β treatment reduced the numbers of proliferating NPCs, an effect prevented by the IL‐1R1 receptor antagonist. LDH and MTT assays, and western blot analysis for cleaved caspase 3 and poly(ADP‐ribose) polymerase, confirmed that this was not due to an increase in cell death but rather an induction of differentiation. To further study the effects of IL‐1β on cell fate determination, we differentiated NPCs in the presence and absence of IL‐1β. Il‐1β promoted gliogenesis and inhibited neurogenesis, an effect that required p38‐MAPK kinase signalling. In summary, these data show that exposure of NPCs to IL‐1β affects their development. This necessitates an examination of the consequences that maternal immune system activation during pregnancy has on the cellular architecture of the developing brain.

Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries

“…These results also provide evidence that IL-1 is either the initiator of the molecular cascades leading to brain damage, or has a central role in the regulation of these events, since the use of a specific antagonist confers protection for most of the parameters studied. This is in agreement with other reports, which showed the neurotoxic consequence of IL-1 (Cai et al, 2004;Crampton et al, 2011;Favrais et al, 2011;Girard et al, 2008;Green et al, 2012), and also with reports on the neuroprotective potential of IL-1Ra administration seen in experimental models of neonatal brain injury induced by pure HI in rodents at a later stage of development, equivalent to term human newborns (Hagberg et al, 1996;Martin et al, 1994). Thus, even if the mechanisms leading to brain damage are known to differ across developmental stages (Anthony et al, 1997;Brochu et al, 2011), IL-1Ra appears to exert its beneficial effects when administered in models of LPS and/or HI induced brain insults, occurring (at least for HI) either in the early preterm or term brain.…”

“…Our results demonstrated a specific role of IL-1 in inflammatory-driven decreased neurogenesis in the hippocampus. This phenomenon was previously shown in other neurological conditions, including depression and stress (Covey et al, 2011;Crampton et al, 2011;Green et al, 2012;Yang and Levison, 2007;Zunszain et al, 2012). The fact that in our model, there was no additive effect when LPS and HI were combined suggest that they act through the same pathway or have redundant function, both through IL-1, with effects already maximal on their own.…”

“…However, such early intervention is limited in humans due to the lack of sensitive antenatal diagnostic tools to detect fetal conditions needing treatment. The present study opens new avenues for postnatal treatment aiming to protect against the effects of prenatal exposure to inflammation, an important risk factor now increasingly associated with several neurodevelopmental diseases (Boksa, 2010;Crampton et al, 2011;Girard et al, 2010b;Meyer, 2011;Paris et al, 2011;Stolp et al, 2011). Postnatal treatment would be a possible option in human neonates since diagnosis is easier after birth; for example through immediate postnatal placental evaluation.…”

“…We first focused on the impact of perinatal insults on the neuronal stem cell population since these cells have been shown to be vulnerable to early-life stressors (Crampton et al, 2011;Graciarena et al, 2010). The number of DCX + cells (a marker of neuronal stem cell), as well as their staining intensity, was decreased in the hippocampal dentate gyrus (DG) after exposure to LPS, HI or LPS + HI (Fig.…”

A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson’s Disease

“…Western blotting was carried out as described (Crampton et al 2012). Cells were lysed in radioimmunoprecipitation assay (RIPA) buffer (50μl RIPA per 1×10 6 cells; 50mM Tris-HCL; 150mM NaCl, 1% Triton X-100, 1mM EDTA, 1mM NaF, 1mM Na 3 VO 4 , 1μg/ml leupeptin and 1μg/ml pepstatin) for 1h on ice, and insoluble debris was removed by centrifugation.…”