Microglia Stimulate Zebrafish Brain Repair Via a Tumor Necrosis Factor-α-Initiated Inflammatory Cascade

Abstract

The adult zebrafish brain, unlike mammals, has a remarkable regenerative capacity. Although inflammation inhibits regeneration in mammals, it is necessary for zebrafish brain repair. Microglia are resident brain immune cells that regulate the inflammatory response. To explore the microglial role in repair, we used liposomal clodronate and colony stimulating factor-1 receptor (csf1r) inhibition to suppress microglia during brain injury. We found that microglial ablation inhibited injury-induced neurogenesis and regeneration. Microglial suppression specifically attenuated cell proliferation at the progenitor cell amplification stage of neurogenesis. Notably, the loss of microglia impaired phospho-stat3 (signal transducer and activator of transcription 3) and ß-catenin signaling by altering tumor necrosis factor-α expression after injury, and the ectopic activation of stat3 and ß-catenin rescued neurogenesis defects caused by microglial loss. Leukocytes also accumulated after microglial ablation, potentially hindering the resolution of inflammation. These findings reveal specific roles of microglia and inflammatory signaling during zebrafish telencephalic regeneration that should provide strategies to improve mammalian brain repair.

Cellular Mechanisms Participating in Brain Repair of Adult Zebrafish and Mammals after Injury

“…Interestingly, the Gata3 transcription factor is mainly expressed by RGCs but is also detected in L-plastin positive microglia [ 131 ], pointing again to an important role of the inflammatory response (leukotriene/gata 3 [ 131 ]). In the same line of evidence, the new data obtained demonstrate the role of microglia activation and TNF-α in regenerative neurogenesis in zebrafish [ 96 ].…”

“…The general recruitment of microglia/immune cells after stab wound injury of the zebrafish telencephalon is shown in Figure 3 . Recently, it was confirmed in zebrafish that microglia recruitment peaks at 1 dpl before it declines, remaining still significantly up-regulated at 4 dpl [ 96 ]. As in mammals, pro-inflammatory molecules (i.e., interleukins Il-1β, Il-6, Il-8, and TNF-α) secreted in part, by microglia have an impact on NSC plasticity, regeneration and neuronal repair, namely in injury-induced neurogenesis in zebrafish [ 71 , 96 ].…”

“…Recently, it was confirmed in zebrafish that microglia recruitment peaks at 1 dpl before it declines, remaining still significantly up-regulated at 4 dpl [ 96 ]. As in mammals, pro-inflammatory molecules (i.e., interleukins Il-1β, Il-6, Il-8, and TNF-α) secreted in part, by microglia have an impact on NSC plasticity, regeneration and neuronal repair, namely in injury-induced neurogenesis in zebrafish [ 71 , 96 ]. Although the exact contribution of microglia in brain repair mechanisms is still poorly understood in zebrafish, new data recently highlight it [ 96 ].…”

“…As in mammals, pro-inflammatory molecules (i.e., interleukins Il-1β, Il-6, Il-8, and TNF-α) secreted in part, by microglia have an impact on NSC plasticity, regeneration and neuronal repair, namely in injury-induced neurogenesis in zebrafish [ 71 , 96 ]. Although the exact contribution of microglia in brain repair mechanisms is still poorly understood in zebrafish, new data recently highlight it [ 96 ]. Indeed, the inhibition of microglia activation during zebrafish brain injury leads to a decreased expression of TNF-α and phospho-stat3/β-catenin signaling, which results in a lower proliferation of neural progenitor/stem cells and a lower number of newborn neurons without affecting differentiation [ 96 ].…”

“…Although the exact contribution of microglia in brain repair mechanisms is still poorly understood in zebrafish, new data recently highlight it [ 96 ]. Indeed, the inhibition of microglia activation during zebrafish brain injury leads to a decreased expression of TNF-α and phospho-stat3/β-catenin signaling, which results in a lower proliferation of neural progenitor/stem cells and a lower number of newborn neurons without affecting differentiation [ 96 ]. These new data decipher the key roles of microglia in brain repair mechanisms.…”