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T cell deficiency in spinal cord injury: altered locomotor recovery and whole-genome transcriptional analysis.

Satzer D, Miller C, Maxon J, Voth J, DiBartolomeo C, Mahoney R, Dutton JR, Low WC, Parr AM - BMC Neurosci (2015)

Bottom Line: To explain variable locomotor outcome, we assessed whole-genome expression using RNA sequencing, in the acute (1 week post-injury) and chronic (8 weeks post-injury) phases of recovery.Immunostaining for macrophage markers revealed no T cell-dependent difference in the acute macrophage infiltrate.T cell inhibition combined with other neuroprotective treatment may thus be a promising therapeutic avenue.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, University of Minnesota, D429 Mayo Memorial Building, MMC 96, 420 Delaware Street, SE, Minneapolis, MN, 55455, USA. satz0002@umn.edu.

ABSTRACT

Background: T cells undergo autoimmunization following spinal cord injury (SCI) and play both protective and destructive roles during the recovery process. T cell-deficient athymic nude (AN) rats exhibit improved functional recovery when compared to immunocompetent Sprague-Dawley (SD) rats following spinal cord transection.

Methods: In the present study, we evaluated locomotor recovery in SD and AN rats following moderate spinal cord contusion. To explain variable locomotor outcome, we assessed whole-genome expression using RNA sequencing, in the acute (1 week post-injury) and chronic (8 weeks post-injury) phases of recovery.

Results: Athymic nude rats demonstrated greater locomotor function than SD rats only at 1 week post-injury, coinciding with peak T cell infiltration in immunocompetent rats. Genetic markers for T cells and helper T cells were acutely enriched in SD rats, while AN rats expressed genes for Th2 cells, cytotoxic T cells, NK cells, mast cells, IL-1a, and IL-6 at higher levels. Acute enrichment of cell death-related genes suggested that SD rats undergo secondary tissue damage from T cells. Additionally, SD rats exhibited increased acute expression of voltage-gated potassium (Kv) channel-related genes. However, AN rats demonstrated greater chronic expression of cell death-associated genes and less expression of axon-related genes. Immunostaining for macrophage markers revealed no T cell-dependent difference in the acute macrophage infiltrate.

Conclusions: We put forth a model in which T cells facilitate early tissue damage, demyelination, and Kv channel dysregulation in SD rats following contusion SCI. However, compensatory features of the immune response in AN rats cause delayed tissue death and limit long-term recovery. T cell inhibition combined with other neuroprotective treatment may thus be a promising therapeutic avenue.

No MeSH data available.


Related in: MedlinePlus

Volcano plots for differential gene expression in the acute and chronic phases of SCI. Colors represent Q < 0.05 (red) and Q > 0.05 (black) for differential expression testing. The overall magnitude of differential gene expression was greater in the acute phase, as evidenced by a larger median absolute value of log2FC (1.27 acute versus 0.99 chronic; P < 0.001) for differentially expressed genes. FC fold change (AN FKPM divided by SD FKPM). Q, false discovery rate-adjusted P value
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Fig3: Volcano plots for differential gene expression in the acute and chronic phases of SCI. Colors represent Q < 0.05 (red) and Q > 0.05 (black) for differential expression testing. The overall magnitude of differential gene expression was greater in the acute phase, as evidenced by a larger median absolute value of log2FC (1.27 acute versus 0.99 chronic; P < 0.001) for differentially expressed genes. FC fold change (AN FKPM divided by SD FKPM). Q, false discovery rate-adjusted P value

Mentions: A total of 14,911 genes were identified by RNA-seq: 14,565 in the acute phase and 14,567 in the chronic phase. Read mapping statistics for each sample are summarized in Table 1. Statistical significance for differential gene expression was determined based upon the Q value (false discovery rate-adjusted P value). Magnitude of differential expression was quantified as fold change (FC), equal to AN FKPM divided by SD FKPM. Volcano plots of statistical significance (−log10Q) versus difference magnitude (log2FC) reveal that the magnitude of differential gene expression was larger in the acute phase (Fig. 3). The median absolute value of log2FC for differentially expressed genes was 1.27 in the acute phase, compared to 0.99 in the chronic phase (P < 0.001 for Mann–Whitney U test).Table 1


T cell deficiency in spinal cord injury: altered locomotor recovery and whole-genome transcriptional analysis.

Satzer D, Miller C, Maxon J, Voth J, DiBartolomeo C, Mahoney R, Dutton JR, Low WC, Parr AM - BMC Neurosci (2015)

Volcano plots for differential gene expression in the acute and chronic phases of SCI. Colors represent Q < 0.05 (red) and Q > 0.05 (black) for differential expression testing. The overall magnitude of differential gene expression was greater in the acute phase, as evidenced by a larger median absolute value of log2FC (1.27 acute versus 0.99 chronic; P < 0.001) for differentially expressed genes. FC fold change (AN FKPM divided by SD FKPM). Q, false discovery rate-adjusted P value
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4635574&req=5

Fig3: Volcano plots for differential gene expression in the acute and chronic phases of SCI. Colors represent Q < 0.05 (red) and Q > 0.05 (black) for differential expression testing. The overall magnitude of differential gene expression was greater in the acute phase, as evidenced by a larger median absolute value of log2FC (1.27 acute versus 0.99 chronic; P < 0.001) for differentially expressed genes. FC fold change (AN FKPM divided by SD FKPM). Q, false discovery rate-adjusted P value
Mentions: A total of 14,911 genes were identified by RNA-seq: 14,565 in the acute phase and 14,567 in the chronic phase. Read mapping statistics for each sample are summarized in Table 1. Statistical significance for differential gene expression was determined based upon the Q value (false discovery rate-adjusted P value). Magnitude of differential expression was quantified as fold change (FC), equal to AN FKPM divided by SD FKPM. Volcano plots of statistical significance (−log10Q) versus difference magnitude (log2FC) reveal that the magnitude of differential gene expression was larger in the acute phase (Fig. 3). The median absolute value of log2FC for differentially expressed genes was 1.27 in the acute phase, compared to 0.99 in the chronic phase (P < 0.001 for Mann–Whitney U test).Table 1

Bottom Line: To explain variable locomotor outcome, we assessed whole-genome expression using RNA sequencing, in the acute (1 week post-injury) and chronic (8 weeks post-injury) phases of recovery.Immunostaining for macrophage markers revealed no T cell-dependent difference in the acute macrophage infiltrate.T cell inhibition combined with other neuroprotective treatment may thus be a promising therapeutic avenue.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, University of Minnesota, D429 Mayo Memorial Building, MMC 96, 420 Delaware Street, SE, Minneapolis, MN, 55455, USA. satz0002@umn.edu.

ABSTRACT

Background: T cells undergo autoimmunization following spinal cord injury (SCI) and play both protective and destructive roles during the recovery process. T cell-deficient athymic nude (AN) rats exhibit improved functional recovery when compared to immunocompetent Sprague-Dawley (SD) rats following spinal cord transection.

Methods: In the present study, we evaluated locomotor recovery in SD and AN rats following moderate spinal cord contusion. To explain variable locomotor outcome, we assessed whole-genome expression using RNA sequencing, in the acute (1 week post-injury) and chronic (8 weeks post-injury) phases of recovery.

Results: Athymic nude rats demonstrated greater locomotor function than SD rats only at 1 week post-injury, coinciding with peak T cell infiltration in immunocompetent rats. Genetic markers for T cells and helper T cells were acutely enriched in SD rats, while AN rats expressed genes for Th2 cells, cytotoxic T cells, NK cells, mast cells, IL-1a, and IL-6 at higher levels. Acute enrichment of cell death-related genes suggested that SD rats undergo secondary tissue damage from T cells. Additionally, SD rats exhibited increased acute expression of voltage-gated potassium (Kv) channel-related genes. However, AN rats demonstrated greater chronic expression of cell death-associated genes and less expression of axon-related genes. Immunostaining for macrophage markers revealed no T cell-dependent difference in the acute macrophage infiltrate.

Conclusions: We put forth a model in which T cells facilitate early tissue damage, demyelination, and Kv channel dysregulation in SD rats following contusion SCI. However, compensatory features of the immune response in AN rats cause delayed tissue death and limit long-term recovery. T cell inhibition combined with other neuroprotective treatment may thus be a promising therapeutic avenue.

No MeSH data available.


Related in: MedlinePlus