Infiltration of circulating monocyte contributes as an important source of bone morphogenetic protein 4 at the early stage of spinal cord injury

Background Bone morphogenetic protein-4 (BMP4) plays a critical role in regulating neuronal and glial activity in the course of spinal cord injury (SCI). However, the underlying cause and cellular source of the BMP4 accumulation at the injured spinal cord remains unclear.
 Method Firstly, the SCI patients and healthy donors were enrolled to test their plasma concentrations of BMP2/4/7 and the antagonist Noggin using enzyme linked immunosorbent assay (ELISA). Secondly, rats were randomly divided into 3 groups: the Sham group (T9 laminectomy without SCI), the SCI group and the SCI+CLL group (circulating monocytes depletion before SCI). For each group, Basso-Beattie-Bresnahan (BBB) scales and immuno-histochemistry were employed to evaluate the functional and histological changes; ELISA was conducted to test the expression patterns of BMP4, Noggin and neurofilament light polypeptide (NEFL) both in blood and cerebrospinal fluid (CSF); western blotting and flow cytometry were further performed to investigate the BMP4 expressions in the spinal cord, and particularly in the circulating monocytes and infiltrating monocyte-derived macrophages (MDMs) respectively.
 Results Firstly, the level of BMP4, instead of BMP2/7 was statistically higher in the SCI patients than in the healthy donors. Secondly, compared with the Sham group, rats in the SCI group developed a persistent decline in the BBB scores, together with evident necrosis and the accumulation of mononuclear cells at the contusion site. Additionally, both plasma and CSF levels of BMP4, Noggin and NEFL displayed notable elevations throughout two weeks after SCI, and positive correlations could be found between blood and CSF in all indicators above. Importantly, BMP4 expression displayed upregulation in the injured spinal cord, and the percentage of BMP4 positive circulating monocytes and infiltrating MDMs were both higher in the SCI group than in the Sham group. Finally, in the SCI+CLL group, depletion of circulating monocytes effectively relieved BMP4 accumulation in the injured spinal cord.
 Conclusion Following SCI, infiltrating MDMs provide an important source of BMP4 in the injured spinal cord. Depletion of circulating monocytes effectively downregulates BMP4 levels in the spinal cord at the early stage of SCI, which might serve as a potential therapeutic target.