IL-10 regulates adult neurogenesis by modulating ERK and STAT3 activity

This seems to be good but WHO is going to follow up with translational research that creates dosages/application methods and timeframes for survivors?
http://journal.frontiersin.org/article/10.3389/fncel.2015.00057/full?

Leticia Pereira^1,2, Miriam Font-Nieves^1,2, Chris Van den Haute^3,4, Veerle Baekelandt³, Anna M. Planas^1,2 and Esther Pozas^1,2*

• ¹Unit of Brain Ischemia, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
• ²Department of Brain Ischemia and Neurodegeneration, Institute of Biomedical Research of Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain
• ³Laboratory for Neurobiology and Gene Therapy, Faculty of Medicine, KU Leuven, Leuven, Belgium
• ⁴Leuven Viral Vector Core, KU Leuven, Leuven, Belgium

The adult subventricular zone (SVZ) contains Nestin+ progenitors that differentiate mainly into neuroblasts. Our previous data showed that interleukin-10 (IL-10) regulates SVZ adult neurogenesis by up-regulating the expression of pro-neural genes and modulating cell cycle exit. Here we addressed the specific mechanism through which IL-10 carries out its signaling on SVZ progenitors. We found that, in vitro and in vivo, IL-10 targets Nestin+ progenitors and activates the phosphorylation of ERK and STAT3. The action of IL-10 on Nestin+ progenitors is reversed by treatment with a MEK/ERK inhibitor, thus restoring neurogenesis to normal levels. Silencing STAT3 expression by lentiviral vectors also impaired neurogenesis by blocking the effects of IL-10. Our findings unveil ERK and STAT3 as effectors of IL-10 in adult SVZ neurogenesis.

Introduction

Postnatal neurogenesis takes place in restricted regions or niches in the adult brain. The SVZ lining the LVs is one of the main neurogenenic niches in the adult brain. The niche is composed by supporting cells, the vasculature and three progenitor cell types: slow-cycling glial-like NSCs or type B cells (GFAP+); TACs or type C cells (Ki67+, and Mash1+), and the more differentiated neuroblasts (type A cells; PSA-NCAM+; DCX+; TUBB3+) that migrate over long distances through the RMS to reach the olfactory bulb, where they finally become mainly GABAergic interneurons (Lois and Alvarez-Buylla, 1994; Doetsch and Alvarez-Buylla, 1996; Doetsch et al., 1997; Merkle et al., 2004; Ihrie et al., 2011). Nestin labels type B and C cells and a sub-population of immature committed neuroblasts (Doetsch et al., 1997; Perez-Asensio et al., 2013). The SVZ niche is unique in spatial localization and molecular characteristics. The relationships between the different cell types, the cerebrospinal fluid (CSF), and the vasculature modulate the molecular signals that regulate self-renewal, proliferation, the identity of VZ-SVZ-derived progeny, the integration of some intrinsic mechanisms (Guillemot, 2007; Lim et al., 2009; Ihrie et al., 2011).

Interleukin-10 (IL-10) is a general anti-inflammatory molecule that contributes to maintaining the pro- and anti-inflammatory balance in the body (Pestka et al., 2004; Saraiva and O’Garra, 2010; Ouyang et al., 2011). Recently, we demonstrated a new physiological role of this cytokine as a relevant factor that regulates postnatal neurogenesis. We deciphered how IL-10 targets the population of Nestin+ progenitors located in the dorsal SVZ, where it regulates the expression of undifferentiated neural progenitor markers, cell cycle activity, and the production of new neuroblasts (Perez-Asensio et al., 2013).

Here we aimed to identify the specific intracellular mechanism through which IL-10 acts specifically on adult Nestin+ progenitors. Our results show that IL-10 regulates the activation of ERK and STAT3 in Nestin+ progenitors and that this activity is required for IL-10 to exert its actions on neural progenitors.

Full article at link.