Abstract
BackgroundSecondary damage after spinal cord injury (SCI) is characterized by a cascade of events including hemorrhage, apoptosis, oxidative stress, and inflammation which increase the lesion size which can influence the functional impairment. Thus, identifying specific mechanisms attributed to secondary injury is critical in minimizing tissue damage and improving neurological outcome. In this work, we are investigating the role of CCL3 (macrophage inflammatory protein 1-α, MIP-1α), a chemokine involved in the recruitment of inflammatory cells, which plays an important role in inflammatory conditions of the central and peripheral nervous system.MethodsA mouse model of lower thoracic (T11) spinal cord contusion injury was used. We assessed expression levels of CCL3 and its receptors on the mRNA and protein level and analyzed changes in locomotor recovery and the inflammatory response in the injured spinal cord of wild-type and CCL3−/− mice.ResultsThe expression of CCL3 and its receptors was increased after thoracic contusion SCI in mice. We then examined the role of CCL3 after SCI and its direct influence on the inflammatory response, locomotor recovery and lesion size using CCL3−/− mice. CCL3−/− mice showed mild but significant improvement of locomotor recovery, a smaller lesion size and reduced neuronal damage compared to wild-type controls. In addition, neutrophil numbers as well as the pro-inflammatory cytokines and chemokines, known to play a deleterious role after SCI, were markedly reduced in the absence of CCL3.ConclusionWe have identified CCL3 as a potential target to modulate the inflammatory response and secondary damage after SCI. Collectively, this study shows that CCL3 contributes to progressive tissue damage and functional impairment during secondary injury after SCI.
Highlights
Secondary damage after spinal cord injury (SCI) is characterized by a cascade of events including hemorrhage, apoptosis, oxidative stress, and inflammation which increase the lesion size which can influence the functional impairment
Gene expression of Chemokine ligand 3 (CCL3) is upregulated after SCI We first assessed changes in the expression of CCL3 and the receptors CCR1, CCR4, and CCR5 in the injured spinal cord of female C57BL/6 mice after a moderate contusion injury (50 kdyn) at 1 and 6 h, and 1, 3, 7, 14, and 28 days following the injury
Protein expression of CCL3 is upregulated after SCI we examined the protein concentration of CCL3 and its receptors at the lesion site at several timepoints following SCI
Summary
Secondary damage after spinal cord injury (SCI) is characterized by a cascade of events including hemorrhage, apoptosis, oxidative stress, and inflammation which increase the lesion size which can influence the functional impairment. Pelisch et al Journal of Neuroinflammation (2020) 17:362 oxygen species, pro-inflammatory cytokines, and chemokines [10, 11] such as CCL2, CXCL1, CXCL2, and CCL20 These chemokines have been reported to play a complex role in the activation and attraction of immune cells after SCI [12, 13]. There is considerable evidence that CCL3 impacts CNS inflammation through regulation of macrophages and astrocytes It is highly expressed in lesions of multiple sclerosis (MS) [22,23,24] and in an animal model of MS, experimental allergic encephalomyelitis (EAE), where the onset of the disease coincides with the mRNA expression of CCL3 [25]. It has been implicated in neuropathic pain following both peripheral nerve injury [36] and SCI [37], the role of CCL3 after SCI and its direct influence on inflammation, injury progression and functional recovery have not yet been described
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