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Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level.

ABSTRACT: Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner.

SUBMITTER: Brommer B

PROVIDER: S-EPMC5014125 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level.

Brommer Benedikt B Engel Odilo O Kopp Marcel A MA Watzlawick Ralf R Müller Susanne S Prüss Harald H Chen Yuying Y DeVivo Michael J MJ Finkenstaedt Felix W FW Dirnagl Ulrich U Liebscher Thomas T Meisel Andreas A Schwab Jan M JM

Brain : a journal of neurology 20160110 Pt 3

Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant mode ...[more]

PMID: 26754788

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Project description:Astrocytes are taking the center stage in neurotrauma and neurological diseases as they appear to play a dominant role in the inflammatory processes associated with these conditions. Previously, we reported that inhibiting NF-?B activation in astrocytes, using a transgenic mouse model (GFAP-I?B?-dn mice), results in improved functional recovery, increased white matter preservation and axonal sparing following spinal cord injury (SCI). In the present study, we sought to determine whether this improvement, due to inhibiting NF-?B activation in astrocytes, could be the result of enhanced oligodendrogenesis in our transgenic mice.To assess oligodendrogenesis in GFAP-I?B?-dn compared to wild-type (WT) littermate mice following SCI, we used bromodeoxyuridine labeling along with cell-specific immuno-histochemistry, confocal microscopy and quantitative cell counts. To further gain insight into the underlying molecular mechanisms leading to increased white matter, we performed a microarray analysis in naïve and 3 days, 3 and 6 weeks following SCI in GFAP-I?B?-dn and WT littermate mice.Inhibition of astroglial NF-?B in GFAP-I?B?-dn mice resulted in enhanced oligodendrogenesis 6 weeks following SCI and was associated with increased levels of myelin proteolipid protein compared to spinal cord injured WT mice. The microarray data showed a large number of differentially expressed genes involved in inflammatory and immune response between WT and transgenic mice. We did not find any difference in the number of microglia/leukocytes infiltrating the spinal cord but did find differences in their level of expression of toll-like receptor 4. We also found increased expression of the chemokine receptor CXCR4 on oligodendrocyte progenitor cells and mature oligodendrocytes in the transgenic mice. Finally TNF receptor 2 levels were significantly higher in the transgenic mice compared to WT following injury.These studies suggest that one of the beneficial roles of blocking NF-?B in astrocytes is to promote oligodendrogenesis through alteration of the inflammatory environment.

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Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level.

Publications

Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level.

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