CCL28 promotes locomotor recovery after spinal cord injury via recruiting regulatory T cells

Abstract

Background: Chemokines play a key role in post-traumatic inflammation and secondary injury after spinal cord injury (SCI). CCL28, the chemokine CC-chemokine ligand 28, is involved in the epithelial and mucosal immunity. However, whether CCL28 participates in the physiopathologic processes after SCI remains unclear.Results: CCL28 is upregulated in the spinal cord after SCI. In addition, neutralizing antibodies against IL-1β or TNF-α, or treatment of ML120B, a selective inhibitor of IKK-β, remarkably decrease CCL28 upregulation, suggesting that CCL28 upregulation relies on NF-κB pathway activated by IL-1β and TNF-α after SCI. Moreover, CD4+CD25+FOXP3+ regulatory T (Treg) cells that express CCR10, a receptor of CCL28, are enriched in the spinal cord after SCI. We further demonstrate that the spinal cord recruits Treg cells through CCL28-CCR10 axis, which in turn function to suppress immune response and promote locomotor recovery after SCI. In contrast, neutralizing CCL28 or CCR10 reduces Treg cell recruitment and delays locomotor recovery.Methods: The neutralizing antibodies and recombinant CCL28 were injected intraspinally into the mice prior to SCI, which was established via hemitransection. RT-qPCR analysis was performed to determine transcript level, and Western blot analysis and ELISA assay were used to detect protein expression. Immune cells were analyzed by flow cytometry and visualized by immunofluorescence. The chemotaxis was assessed by in vitro transwell migration assay. The mouse locomotor activity was assessed via the Basso Mouse Scale (BMS) system.Conclusions: These results indicate that NF-κB pathway-regulated CCL28 production plays a protective role after SCI through recruiting CCR10-expressing and immunosuppressive Treg cells, and suggest that interfering CCL28-CCR10 axis might be of potential clinical benefit in improving SCI recovery.

Zinc attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury by activating Nrf2/GPX4 defense pathway

“…Cerebral ischemia‐reperfusion injury is closely linked to the inflammatory response, and it is also involved in spinal cord injury. 40 , 41 , 42 Inflammation can be effectively controlled, and we believe the results will be surprising. Interestingly, it has been reported that GPX4 is involved in inflammation in a variety of traumatic conditions.…”

“…Cerebral ischemia‐reperfusion injury is closely linked to the inflammatory response, and it is also involved in spinal cord injury 40–42 . Inflammation can be effectively controlled, and we believe the results will be surprising.…”

T‐cell infiltration, contribution and regulation in the central nervous system post‐traumatic injury

“…However, one study showed that purified monocytes from injured brains reduced the production of Treg cells in a mixed lymphocyte reaction in vitro 3 . Neutralizing C‐C motif chemokine ligand 28(CCL28) or CCR10 decreases the recruitment of Treg cells and delays the healing of locomotor function in mice after SCI 84 . Meanwhile, Sirtuin 4 inhibits AMP‐activated protein kinase signalling in Treg cells in vitro.…”

“…The spinal cord recruits CCR10‐expressing Treg cells through CCL28‐CCR10 axis, suppressing immune response and promoting recovery. 103 …”

“… 3 Neutralizing C‐C motif chemokine ligand 28(CCL28) or CCR10 decreases the recruitment of Treg cells and delays the healing of locomotor function in mice after SCI. 84 Meanwhile, Sirtuin 4 inhibits AMP‐activated protein kinase signalling in Treg cells in vitro. It might be a mechanism that inhibits the anti‐neuroinflammatory activity of Treg cells in traumatic SCI in mice.…”