Macropinocytosis contributes to foamy macrophage formation and IL-1beta production after spinal cord injury

Traumatic spinal cord injury (SCI) is a devastating trauma that leads to irreversible motor and sensory dysfunction and with limited therapeutic options. Numerous studies have shown that macrophages transform into foam cells after phagocytosing myelin debris through receptor-dependent pathway post SCI. However, there are still fundamental gaps of receptor-independent mechanisms leading to foam cell formation. Herein, we investigated the effect of macropinocytosis in internalization of myelin debris. The murine SCI model was generated to determine the critical role of myelin debris internalization in foamy macrophages formation in vivo. The potential impact of macropinocytosis was explored using qPCR, western blotting, TEM, RNA sequencing and immunofluorescence after treating macrophages with myelin debris in vitro. We found that internalization of myelin debris led to the formation of foamy cells, which are predominantly composed of macrophages. Meanwhile, both in vivo and in vitro studies revealed that macropinocytosis plays a key role in engulfing myelin debris to form foamy macrophages after SCI, which was not disrupted by receptor-mediated endocytosis. Finally, we identified an important role of macropinocytosis in cholesterol accumulation through activating the NOD-like receptor protein 3 (NLRP3) inflammasome and releasing interleukin-1beta (IL-1beta). Moreover, inhibition of macropinocytosis may improve functional outcomes after SCI by promoting axon regeneration and decreasing neuron apoptosis. Our study reveals a previously unrecognized role of macropinocytosis in foamy macrophage formation post SCI. Targeting macropinocytosis might be a promising therapeutic strategy for SCI.