Brain Behav Immun
We have previously shown that tissue inflammation in the brain can potently inhibit neural stem cell activity and prevent the production of new neurons. In this study, we examine the specific influence of an inflammatory signaling molecule called tumor necrosis factor alpha (TNFa). TNFa is one of the primary pro-inflammatory signaling molecules that establishes and maintains damaging inflammation and we speculated that blocking TNFa may protect stem cells under conditions where injury or degeneration causes inflammation. TNFa can also be beneficial in certain contexts and here we show that the effects of TNFa on stem cells and neurogenesis can be either detrimental or beneficial, depending on whether TNF signals through TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2). Loss of TNFR1 promoted stem cell survival and neurogenesis while loss of TNFR2 was detrimental to stem cells and neurogenesis. Loss of TNFa itself had mixed effects and was ultimately not protective. This illustrates how a single molecule can have multiple roles in neural stem cell biology and cautions against the uninformed use of clinically-approved TNFa blocking agents in an attempt to protect stem cells and neurogenesis in the context of inflammation caused by neurodegenerative disease or brain injury.
Tumor necrosis factor alpha (TNFalpha) is a potent inhibitor of neurogenesis in vitro but here we show that TNFalpha signaling has both positive and negative effects on neurogenesis in vivo and is required to moderate the negative impact of cranial irradiation on hippocampal neurogenesis. In vitro, basal levels of TNFalpha signaling through TNFR2 are required for normal neural progenitor cell proliferation while basal signaling through TNFR1 impairs neural progenitor proliferation. TNFR1 also mediates further reductions in proliferation and elevated cell death following exposure to recombinant TNFalpha. In vivo, TNFR1(-/-) and TNFalpha(-/-) animals have elevated baseline neurogenesis in the hippocampus, whereas absence of TNFR2 decreases baseline neurogenesis. TNFalpha is also implicated in defects in neurogenesis that follow radiation injury but we find that loss of TNFR1 has no protective effects on neurogenesis and loss of TNFalpha or TNFR2 worsened the effects of radiation injury on neurogenesis. We conclude that the immunomodulatory signaling of TNFalpha mediated by TNFR2 is more significant to radiation injury outcome than the proinflammatory signaling mediated through TNFR1.