Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis

Tumor necrosis factor alpha (TNF alpha) is a potent inhibitor of neurogenesis in vitro but here we show that TNF alpha 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 TNF alpha 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 TNF alpha. In vivo, TNFR1(-/-) and TNF alpha(-/-) animals have elevated baseline neurogenesis in the hippocampus, whereas absence of TNFR2 decreases baseline neurogenesis. TNF alpha 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 TNF alpha or TNFR2 worsened the effects of radiation injury on neurogenesis. We conclude that the immunomodulatory signaling of TNF alpha mediated by TNFR2 is more significant to radiation injury outcome than the proinflammatory signaling mediated through TNFR1. (C) 2013 Elsevier Inc. All rights reserved.