Early Targeting of L-Selectin on Leukocytes Promotes Recovery after Spinal Cord Injury, Implicating Novel Mechanisms of Pathogenesis

McCreedy, Dylan A.; Lee, S.; Sontag, Christopher J.; Weinstein, Philip; Olivas, Andrea D.; Martinez, Aida F.; Fandel, Thomas M.; Trivedi, Alpa; Lowell, Clifford A.; Rosen, Steven D.; Noble-Haeusslein, Linda J.

doi:10.1523/eneuro.0101-18.2018

Cited by 15 publications

(12 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the spinal cord, like in many other injured tissues [79], neutrophils are the first cell type to infiltrate into the tissue, peaking 1 day after injury followed by a quick reduction in numbers [80]. Several studies have identified neutrophils as a promising target after SCI [7,81,82]. However, in other studies, neutrophil depletion has led to impaired recovery and increased tissue damage [83].…”

Section: Discussionmentioning

confidence: 99%

CCL3 contributes to secondary damage after spinal cord injury

Pelisch

Almanza

Stehlik

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background 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. 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. Methods A 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. Results The 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. Conclusion We 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.

show abstract

Section: Discussionmentioning

confidence: 99%

CCL3 contributes to secondary damage after spinal cord injury

Pelisch

Almanza

Stehlik

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…The proteins S100A8 and S100A9 are frequently combined as the antimicrobial dimer calprotectin (Striz and Trebichavsky, 2004). They probably arrive in the injured spinal cord as constituents of myeloid cells, particularly neutrophils (Fleming et al, 2006; Mitchell et al, 2008), which are thought to be deleterious to recovery (McCreedy et al, 2018), although S100A8 and S100A9 can also be induced in macrophages and microglia by neuropathic states (Abe et al, 1999). While there is some indirect evidence that S100A9 promotes recovery from SCI (Roet et al, 2013), but pro-inflammatory effects are more likely the dominant initial action.…”

Section: Discussionmentioning

confidence: 99%

Brainstem-Evoked Transcription of Defensive Genes After Spinal Cord Injury

Jermakowicz

Carballosa-Gautam

Vitores

et al. 2019

Front. Cell. Neurosci.

View full text Add to dashboard Cite

The spinal cord after injury shows altered transcription in numerous genes. We tested in a pilot study whether the nucleus raphé magnus, a descending serotonergic brainstem region whose stimulation improves recovery after incomplete spinal cord injury (SCI), can influence these transcriptional changes. Rats received 2 h of low-frequency electrical stimulation in the raphé magnus 3 days after an impact contusion at segment T8. Comparison groups lacked injuries or activated stimulators or both. Immediately following stimulation, spinal cords were extracted, their RNA transcriptome sequenced, and differential gene expression quantified. Confirming many previous studies, injury primarily increased inflammatory and immune transcripts and decreased those related to lipid and cholesterol synthesis and neuronal signaling. Stimulation plus injury, contrasted with injury alone, caused significant changes in 43 transcripts (39 increases, 4 decreases), all protein-coding. Injury itself decreased only four of these 43 transcripts, all reversed by stimulation, and increased none of them. The non-specific 5-HT7 receptor antagonist pimozide reversed 25 of the 43 changes. Stimulation in intact rats principally caused decreases in transcripts related to oxidative phosphorylation, none of which were altered by stimulation in injury. Gene ontology (biological process) annotations comparing stimulation with either no stimulation or pimozide treatment in injured rats highlighted defense responses to lipopolysaccharides and microorganisms, and also erythrocyte development and oxygen transport (possibly yielding cellular oxidant detoxification). Connectivity maps of human orthologous genes generated in the CLUE database of perturbagen-response transcriptional signatures showed that drug classes whose effects in injured rats most closely resembled stimulation without pimozide include peroxisome proliferator-activated receptor agonists and angiotensin receptor blockers, which are reportedly beneficial in SCI. Thus the initial transcriptional response of the injured spinal cord to raphé magnus stimulation is upregulation of genes that in various ways are mostly protective, some probably located in recently arrived myeloid cells.

show abstract

“…Further, the disruption of circadian outputs persisted beyond 2 dpi, including rhythms of serum CORT, body temperature, and activity (all were disrupted until at least 7 dpi), yet our study only assessed gene expression changes at 2 d postsurgery. Gene expression was assessed at 2 d postsurgery because robust changes in the circadian system were seen at this time, and because early changes in lesion pathology and inflammation likely have strong effects on recovery trajectory (Noble et al, 2002; Kigerl et al, 2009; Gaudet et al, 2018; McCreedy et al, 2018). It is also important, however, to understand how clock and inflammatory gene patterns shift through subacute and chronic times postsurgery.…”

Section: Discussionmentioning

confidence: 99%