The dual roles of chemokines in peripheral nerve injury and repair

Abstract

Peripheral nerve injuries (PNI) occur in approximately 13-23 per 100,000 individuals, predominantly affecting young and middle-aged adults. These injuries often require a lengthy recovery period, placing substantial burdens on healthcare systems and national economies. Current treatment strategies have not significantly shortened this lengthy regenerative process, highlighting the urgent need for innovative therapeutic interventions. Chemokines were originally noted for their powerful ability to recruit immune cells; however, as research has advanced, it has become increasingly evident that their role in peripheral nerve repair has been underestimated. In this review, we provide the first comprehensive overview of chemokine expression and activity during peripheral nerve injury and regeneration. We summarize the existing literature on chemokine family members, detailing their expression patterns and localization in injured nerves to facilitate further mechanistic investigations. For chemokines that remain controversial, such as CXCL1 and CCL2, we critically examine experimental methodologies and discuss factors underlying conflicting results, ultimately affirming their contributions to promoting nerve repair. Importantly, we highlight the dual nature of chemokines: in the early stages of injury, they initiate reparative responses, activate Schwann cells, regulate Wallerian degeneration, and support nerve recovery; but when the axons are connected and the repair enters the later stages, their persistent proinflammatory effects during later stages may impede the healing process. Additionally, we emphasize that certain chemokines, including CXCL5, CXCL12, and CCL2, can act directly on neurons/axons, thereby accelerating axonal regeneration. Future research should focus on precisely mapping the localization and temporal expression profiles of these chemokines and exploring therapeutic approaches.

Keywords: Chemokines; Inflammation; Peripheral nerve injuries.

Fig. 1

Localization of the chemokine family. Neutrophils express CXCR2. Macrophages express CXCR2, CXCR3, CCR2, and CCR4 on the cell surface and secrete CCL2, CCL3, and CCL5. Neurons/axons express CXCR2, CXCR4, and XCR1 on the cell surface and secrete CXCL1, CXCL5, CXCL12, CXCL13, CCL2, CCL3, CCL5, CX3 CL1, and XCL1. Schwann cells express CXCR4 and XCR1 on the cell surface and secrete CXCL1, CXCL12, CCL2, CCL3, and CCL5. Adipose-derived stem cells (ADSCs) express CXCR4, CCR4, CX3 CR1, and XCR1 on the cell surface. CD34⁺ cells and mesenchymal stem cells express CXCR4 on the cell surface. CD45⁺ WBC express XCR1 on the cell surface. Fibroblasts secrete CCL2, CCL3, and CCL5

Fig. 2

Expression and mechanism of action of chemokine family members in PNI. Macrophages: In macrophages, CXCL1/CXCR2 promotes the expression of NLRP3, thereby facilitating the release of IL- 1β. CCL2/CCR2 activates signaling pathways such as the JAK-STAT and Ras pathways to promote M1 polarization. The activation of CX3 CR1 results in the release of NOX2, which enters damaged axons via endocytosis and is transported to the cell body via retrograde transport through an importin-β1-dynein-dependent mechanism. NOX2 oxidizes PTEN, leading to its inactivation and subsequent activation of the PI3 K‒Akt signaling pathway, thus promoting nerve regeneration