Opposite effect of inflammation on subventricular zone versus hippocampal precursors in brain injury

Abstract

Objective Inflammation promotes epidermal wound healing but is considered detrimental to recovery from CNS injury. Sick infants have increased levels of cytokines in their CSF that correlate with poor neurological outcome. In this study we investigated the role of neuroinflammation and more specifically, IL-6, in the amplification of subventricular zone (SVZ) and subgranular zone (SGZ) neural precursors after neonatal brain injury. Methods Neonatal hypoxia/ischemia (H/I) was induced in P6 rat pups and IL-6 was quantified with or without Indomethacin administration. Neural precursor responses were evaluated by neurosphere assays as well as by stereological analyses. Studies were performed to determine how IL-6 and LIF affect SVZ cell expansion, proliferation and self-renewal. Results Consistent with earlier studies, SVZ cells expanded after H/I. Contrary to our expectations, Indomethacin significantly decreased both the initial reactive increase in these precursors as well as their ability to self-renew. By contrast, Indomethacin increased proliferation in the SGZ and lateral SVZ. Indomethacin diminished the accumulation of microglia/macrophages and IL-6 production after H/I. In vitro IL-6 enhanced neurosphere growth, self-renewal and tripotentiality and was more effective than LIF in promoting self-renewal. Enhanced precursor self-renewal also was obtained using PGE2, which is downstream of cyclooxygenase-2 and a target of Indomethacin. Interpretation These data implicate neuroinflammation and in particular IL-6 as a positive effector of primitive neural precursor expansion after neonatal brain injury. These findings have important clinical implications, as Indomethacin and other anti-inflammatory agents are administered to premature infants for a variety of reasons.

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

“…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, the role of inflammation in neural stem cell proliferation is still controversial and might be age-dependent. Recent work by Covey et al revealed that neurogenesis seen in an animal model of HI at P6 was mediated by IL-6 expression and was decreased by broad anti-inflammatory administration (Covey et al, 2011). On the other hand, studies in adult animals showed deleterious effects of inflammatory mediators on neural progenitor proliferation (Monje et al, 2003;Vallières et al, 2002).…”

Neural Stem Cells in the Immature, but Not the Mature, Subventricular Zone Respond Robustly to Traumatic Brain Injury

“…First, many experiments investigating proliferation after injury have focused on the hippocampal subgranular zone [33,34] . However, hippocampal neural precursors are quite different from SVZ neural precursors [32] Thus, it is not surprising that subgranular zone cells respond differently after similar insults compared to SVZ neural precursors. Second, adult mouse SVZ cells proliferate significantly after injury [35] and in our studies the P14-injured mice exhibited higher proliferative rates in both the ipsilateral and contralateral hemispheres compared to P11 rats.…”

“…This suggests that injury signals are produced in the damaged hemisphere and that the larger the injury the greater the stimulus. Another consideration is that injury signals are not only produced by cells residing in the injured tissue, but immune cells attracted to the wound will produce and release cytokines and growth factors that are known to affect SVZ cells [27][28][29][30][31][32] .…”

Sterile Neuroinflammation and Strategies for Therapeutic Intervention

“…Brain injury and neurodegeneration are characterized by the increase in amount of proinflammatory cytokines and numbers of activated microglia [57]. Since inflammation is a key pathological change observed in these conditions [58], it is a valuable therapeutic target in the treatment of brain injuries and neurodegeneration.…”