CCL3 contributes to secondary damage after spinal cord injury

Traumatic spinal cord injury (SCI) is a devastating neurological condition that results in a loss of motor and sensory function. Although extensive research to develop treatments for SCI has been performed, to date, none of these treatments have produced a meaningful amount of functional recovery after injury. The primary injury is caused by the initial trauma to the spinal cord and results in ischemia, oxidative damage, edema, and glutamate excitotoxicity. This process initiates a secondary injury cascade, which starts just a few hours post-injury and may continue for more than 6 months, leading to additional cell death and spinal cord damage. Inflammation after SCI is complex and driven by a diverse set of cells and signaling molecules. In this review, we utilize an extensive literature survey to develop the timeline of local immune cell and cytokine behavior after SCI in rodent models. We discuss the precise functional roles of several key cytokines and their effects on a variety of cell types involved in the secondary injury cascade. Furthermore, variations in the inflammatory response between rats and mice are highlighted. Since current SCI treatment options do not successfully initiate functional recovery or axonal regeneration, identifying the specific mechanisms attributed to secondary injury is critical. With a more thorough understanding of the complex SCI pathophysiology, effective therapeutic targets with realistic timelines for intervention may be established to successfully attenuate secondary damage.

show abstract

“…Expression induced by pro-inflammatory stimulators, such as LPS, TNFα and IL-1β, and neuronal injury [ 163 ]…”

Section: Main Textmentioning

confidence: 99%

Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration

Hellenbrand

Quinn

Piper

et al. 2021

J Neuroinflammation

286

175

View full text Add to dashboard Cite

show abstract

“…Besides, we also observed that CCL3 was also inhibited by cordycepin. CCL3 recruits neutrophils through binding to the CCR1 on the neutrophil surface, neutrophil recruitment in mice with CCL3 de ciency signi cantly decreased as reported [65,66]. Moreover, TNF-α and IL-1β mobilize neutrophils and induce adhesion molecule expression on cerebral endothelial and glial cells, thereby promoting neutrophil accumulation and migration into CNS [65,67,68].…”

Section: Discussionmentioning

confidence: 71%

Cordycepin Confers long-term neuroprotection via inhibiting neutrophil infiltration and neuroinflammation after traumatic brain injury

Wei

Huang

Luo

et al. 2021

Preprint

View full text Add to dashboard Cite

Background Traumatic brain injury (TBI) secondary injury, especially white matter injury (WMI), is highly sensitive to neuroinflammation, which further leads to unfavored long-term outcomes. Although the cross-talk between the three active events, immune cell infiltration, BBB breakdown, and proinflammatory microglial/macrophage polarization, play a role in the vicious cycle, its mechanisms are not fully understood. It has been reported that cordycepin, an extract from cordyceps militaris, can inhibit TBI-induced neuroinflammation although the long-term effects of cordycepin remain unknown. Here, we report our investigation of cordycepin’s long-term neuroprotective function and its underlying immunological mechanism. Methods TBI mice model was established with a controlled cortical impact (CCI) method. Cordycepin was intraperitoneally administered twice daily for a week. Neurological outcomes were assessed by behavioral tests, including grid walking test, cylinder test, wire hang test, and rotarod test. Immunofluorescence staining, transmission electron microscopy, and electrophysiology recording were employed to assess histological and functional lesions. Quantitative-PCR and flow cytometry were used to detect neuroinflammation. The tracers of Sulfo-NHS-biotin and Evans blue were assessed for the Blood-brain barrier (BBB) leakage. Western blot and gelatin zymography were used to analyze protein activity or expression. Neutrophil depletion in vivo was performed via using Ly6G antibody intraperitoneal injection. Results Cordycepin administration ameliorated long-term neurological deficits and reduced neuronal tissue loss in TBI mice. Meanwhile, the long-term integrity of white matter was also preserved, which was revealed in multiple dimensions, such as morphology, histology, ultrastructure, and electrical conductivity. Cordycepin administration inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization after TBI. BBB breach was attenuated by cordycepin administration at 3d after TBI. Cordycepin suppressed the activities of MMP-2 and MMP-9 and the neutrophil infiltration at 3d after TBI. Moreover, neutrophil depletion provided a cordycepin-like effect, and cordycepin administration united with neutrophil depletion didn’t show a benefit of superposition. Conclusions The long-term neuroprotective function of cordycepin was via suppressing neutrophil infiltration, thereby preserving BBB integrity and changing microglia/macrophage polarization. These findings provide significant clinical potentials to improve the quality of life for TBI patients.

show abstract

“…[17]. By binding to receptors on immune cells, CCL3 promotes the production of in ammatory cytokines, and overactive of CCL3 has a direct detrimental effect on the prognosis of the disease [16,24].…”

Section: Discussionmentioning

confidence: 99%

CCL3 aggravates intestinal tissue damage in NEC by promoting macrophage chemotaxis and M1 macrophage polarization.

Yuan

Chen

et al. 2022

Preprint

View full text Add to dashboard Cite

Necrotizing enterocolitis (NEC) is a life-threatening inflammatory gastrointestinal disease in neonates, the mechanism of which is poorly elucidated. Intestinal mucosal barrier imbalance due to excessive inflammatory response is an important endogenous cause of NEC. Our study elucidates a novel mechanism of NEC development, in which CCL3 regulated the chemotaxis, polarization, and function of macrophages to promote NET progression. Our data show that CCL3 is highly expressed in the intestinal tissues of NEC patients and mice and induce macrophage infiltration. Transcriptome data from high-throughput sequencing showed that CCL3 strongly induced macrophages switch into a pro-inflammatory phenotype. Mechanistically, in vivo experiments confirmed that CCL3 induced M1 polarization of macrophages in NEC intestinal tissue, thereby aggravating inflammatory injury of intestinal tissue which can be reversed by anti-CCL3 treatment; in accordance, in vitro experiments showed that CCL3 could significantly enhance the expression of M1-related genes (e.g. iNOS, IRF5, CD86) in both peritoneal macrophages and bone marrow derived macrophages while inhibit the expression of M2-related genes (e.g. Arg-1, FIZZ1, YM1), which could also be reversed by anti-CCl3 treatment. Herein, our study has elucidated a novel mechanism of CCL3 involvement in the pathogenesis of NEC, in which the upregulated CCL3 expression exacerbated inflammatory intestinal damage via regulating macrophage chemotaxis and M1 phenotype polarization, suggesting that blocking CCL3 may be a potential strategy for effective intervention of NEC.

show abstract

CCL3 contributes to secondary damage after spinal cord injury

Cited by 14 publications

References 47 publications

Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration

Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration

Cordycepin Confers long-term neuroprotection via inhibiting neutrophil infiltration and neuroinflammation after traumatic brain injury

CCL3 aggravates intestinal tissue damage in NEC by promoting macrophage chemotaxis and M1 macrophage polarization.

Contact Info

Product

Resources

About