Abstract
BackgroundThe acute phase response (APR) to CNS insults contributes to the overall magnitude and nature of the systemic inflammatory response. Aspects of this response are thought to drive secondary inflammatory pathology at the lesion site, and suppression of the APR can therefore afford some neuroprotection. In this study, we examined the APR in a mouse model of traumatic spinal cord injury (SCI), along with its relationship to neutrophil recruitment during the immediate aftermath of the insult. We specifically investigated the effect of IL-1 receptor antagonist (IL-1RA) administration on the APR and leukocyte recruitment to the injured spinal cord.MethodsAdult female C57BL/6 mice underwent either a 70kD contusive SCI, or sham surgery, and tissue was collected at 2, 6, 12, and 24 hours post-operation. For IL-1RA experiments, SCI mice received two intraperitoneal injections of human IL-1RA (100mg/kg), or saline as control, immediately following, and 5 hours after impact, and animals were sacrificed 6 hours later. Blood, spleen, liver and spinal cord were collected to study markers of central and peripheral inflammation by flow cytometry, immunohistochemistry and qPCR. Results were analysed by two-way ANOVA or student’s t-test, as appropriate.ResultsSCI induced a robust APR, hallmarked by elevated hepatic expression of pro-inflammatory marker genes and a significantly increased neutrophil presence in the blood, liver and spleen of these animals, as early as 2 hours after injury. This peripheral response preceded significant neutrophil infiltration of the spinal cord, which peaked 24 hours post-SCI. Although expression of IL-1RA was also induced in the liver following SCI, its response was delayed compared to IL-1β. Exogenous administration of IL-1RA during this putative therapeutic window was able to suppress the hepatic APR, as evidenced by a reduction in CXCL1 and SAA-2 expression as well as a significant decrease in neutrophil infiltration in both the liver and the injured spinal cord itself.ConclusionsOur data indicate that peripheral administration of IL-1RA can attenuate the APR which in turn reduces immune cell infiltration at the spinal cord lesion site. We propose IL-1RA treatment as a viable therapeutic strategy to minimise the harmful effects of SCI-induced inflammation.
Highlights
Systemic inflammatory response syndrome (SIRS) is a major and frequent complication in trauma patients with a spinal cord injury (SCI)
Previous work from our group has demonstrated that the level of expression of the mRNA for acute phase proteins is a reliable measure of the acute phase response by the liver, and that the levels reflect the subsequent protein expression levels [5, 9]
By 6 hours, the expression of these mRNA species had returned to naïve baseline levels in the sham controls, but they remained increased in the SCI mice (IL-1β p
Summary
Systemic inflammatory response syndrome (SIRS) is a major and frequent complication in trauma patients with a spinal cord injury (SCI). Pro-inflammatory cytokines and chemokines as well as acute phase proteins (APPs) are upregulated as early as 2 hours post-injury [5, 7,8,9,10] These mediators contribute to the mobilisation and priming of leukocytes, facilitating their translocation to sites of CNS injury. Neutrophils are the first peripheral immune cells to be recruited to CNS lesion sites, including in SCI [11], and they are known to release proteases and generate oxidative species [12, 13]. In peripheral trauma, this enables degradation of debris which is beneficial to the host. We investigated the effect of IL1 receptor antagonist (IL-1RA) administration on the APR and leukocyte recruitment to the injured spinal cord
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