Infection of expecting mothers is a putative risk factor for neuropsychiatric disease in human progeny. Infection triggers pro-inflammatory signals, and if prenatal exposure to inflammation creates enduring neurological changes then pro-inflammatory cytokines, such as interleukin-6 (IL-6), could impact fetal brain development (see Cope and Gould). In mice, inhibition of the pro-inflammatory cytokine (IL-6) in pregnant dams injected with a reagent that stimulates antiviral signaling can ameliorate brain defects and behavioral abnormalities in postnatal pups. Gallagher et al. found that two-month-old offspring of pregnant mice injected with a single bolus of IL-6 had increased numbers of proliferating neural progenitor cells (NPCs) in the forebrain subventricular zone (SVZ) as well as increased numbers of olfactory interneurons, which differentiate from these cells. Forebrain precursor cells in fetal brains 1 day after maternal injection of IL-6 or cultured forebrain precursor cells treated acutely with IL-6 exhibited increased cell proliferation and phosphorylation of STAT3 (signal transducer and activator of transcription 3), a target of IL-6 receptor (IL6R) activation. The number of neurosphere-initiating cells and the ability to grow secondary neurospheres after passage in culture was enhanced for SVZ NPCs from brains of postnatal day 7 pups from IL-6–injected dams. Endogenous IL-6 was secreted into the media of cultured embryonic cortical precursor cells, and incubating these cells with a function-blocking IL-6 antibody reduced proliferation. The forebrains of Il6-knockout mice had fewer proliferating precursors, and the precursor cells had reduced ability to form primary and secondary neurospheres in culture. Knockdown of IL6R by siRNA-electroporation in vivo reduced the number of embryonic forebrain precursor cells and increased the number of neurons. Thus, maternal IL-6 exposure enhanced the endogenous IL-6 signaling pathway that is required to promote embryonic forebrain precursor cell self-renewal and prevent premature neuronal differentiation and could be a factor in neurological disease caused by maternal infection.
D. Gallagher, A. A. Norman, C. L. Woodard, G. Yang, A. Gauthier-Fisher, M. Fujitani, J. P. Vessey, G. I. Cancino, N. Sachewsky, K. Woltjen, M. P. Fatt, C. M. Morshead, D. R. Kaplan, F. D. Miller, Transient maternal IL-6 mediates long-lasting changes in neural stem cell pools by deregulating an endogenous self-renewal pathway. Cell Stem Cell 13, 564–576 (2013). [PubMed]
E. C. Cope, E. Gould, Cytokines make an indelible impression on neural stem cells. Cell Stem Cell 13, 507–508 (2013). [PubMed]