CONICET | Buscador de Institutos y Recursos Humanos

Objective: Inhibition of dendritic cell (DC) maturation and activation, and the consequent interference with the normal functioning of cell-mediated immunity, is frequently observed in patients during the chronic phase of traumatic spinal cord injury (SCI). The lack of comprehension of the underlying mechanisms of these effects has prevented the use of immune-based therapies in chronic SCI to avoid further tissue damage and/or to promote tissue regeneration. In the present work we sought to elucidate relevant molecular targets for alternative therapies by performing whole-genome microarray and molecular pathway analyses.Study design: Male subjects were recruited from an ongoing study of health and SCI patients. Subjects with motor complete chronic SCI (> 2 years post-injury) were identified based on low hip bone density. Subjects without SCI and normal hip bone density comprised the comparison group. Microarray analysis using Affymetrix HG-U133A GeneChip® array was performed with RNA extracted from circulating monocytes. Partek Genomic Suite (PGS) software was used to limit the 54,000 gene list to only those genes up-regulated or down-regulated by 2 fold or more with a p value < 0.05 in SCI compared to control. Pathway analyses were performed with Ingenuity Systems IPA software to identify biological pathways of interest involving differentially expressed genes. Genes of interested were then confirmed by quantitative PCR (qPCR).Results: Six SCI subjects and five controls participated in the final analyses. A molecular pathway related to immune cell trafficking was identified as being significantly upregulated in the SCI subjects. Two genes in that network, TMEM176A and TMEM176B, were notable for their magnitudes of overexpression (fold changes of +5.2 and +11.9 respectively). Moreover, qPCR studies confirmed respective fold changes of 9.8 and 18.01.Discussion: DCs have been shown to mediate recovery and/or protective autoimmunity in a variety of central nervous system (CNS) injuries and have the capacity to induce neuroprotection and neurogenesis in stroke patients. High TMEM176A and TMEM176B levels have been shown to prevent DC maturation and to inhibit DC activity in healthy populations. Here, we have demonstrated increased overexpression of both genes in SCI compared to control patients. Thus, we conclude that the role of these two genes in inhibiting protective immune responses should be investigated, particularly as possible targets of therapies designed to promote immune system-mediated neuroprotection and recovery in SCI.