Inflammation is a natural response to injury, characterized by the recruitment of immune cells to the site of damage. This response is essential for clearing debris and facilitating the regeneration of nerve tissues. In this process, macrophages play a pivotal role in the inflammatory response, transitioning from a pro-inflammatory M1 phenotype to a healing M2 phenotype, which is crucial for promoting nerve repair and regeneration (13). Immune cells regulate the intensity and duration of the inflammatory response by releasing various cytokines and chemokines. For instance, pro-inflammatory factors such as IL-1β and TNF-α are highly expressed during the initial stage of injury, clearing myelin debris and initiating the inflammatory response; whereas anti-inflammatory factors such as IL-10 and TGF-β are upregulated during the later stages of repair, inhibiting excessive inflammatory response and promoting tissue repair (14). Additionally, Treg cells have been identified as important modulators that can suppress excessive inflammatory responses, thereby preventing neuropathic pain and promoting a more favorable environment for nerve regeneration (15).

The interaction between the immune system and neuronal cells is vital for axonal regeneration. For example, the blockade of glial inhibitors, combined with the activation of intrinsic neuronal growth pathways, has been demonstrated to induce axonal regeneration (16). This suggests that targeting both immune responses and neuronal growth factors can synergistically enhance recovery after injury. Moreover, the role of macrophages in modulating the environment for axonal growth is significant. Multipotent adult progenitor cells have been shown to shift macrophages from a pro-inflammatory state to an anti-inflammatory state, which not only prevents axonal dieback but also promotes regrowth after spinal cord injury (17).

Immune cells facilitate axonal regeneration through both direct and indirect mechanisms, primarily by secreting a range of growth factors and extracellular matrix proteins. For example, macrophages secrete neurotrophic factors, including NGF, BDNF, and glial cell line-derived neurotrophic factor (GDNF), which directly enhance axonal growth (18). Furthermore, immune cells contribute to the formation of a supportive scaffold for axonal extension by modulating extracellular matrix components within the local microenvironment, such as fibronectin and laminin (19).

The interaction between Schwann cells and immune cells is critical for nerve regeneration. Schwann cells not only provide structural support but also secrete factors that influence macrophage behavior, thereby orchestrating the immune response at the injury site (20). For instance, the secretion of GDNF by Schwann cells can enhance macrophage polarization toward the M2 phenotype, promoting axonal regeneration (21). The dynamic interplay between the immune system and Schwann cells highlights the importance of immune modulation in PNR. Strategies that enhance the recruitment of pro-regenerative macrophages or modulate their polarization could lead to improved outcomes in nerve repair. Understanding these mechanisms provides valuable insights into developing therapeutic interventions aimed at enhancing PNR.

The signaling pathways of immune regulation play a crucial role in PNR, orchestrating the complex interactions between various cell types, including Schwann cells, macrophages, and neurons. The involvement of specific signaling pathways, such as the NF-κB/STAT3 cascade, has been highlighted in regulating axonal growth and immune responses post-injury. NF-κB is activated in sensory neurons following peripheral axotomy and is crucial for promoting axon growth (22). Additionally, the mTOR signaling pathway has been shown to be reactivated in Schwann cells during the dedifferentiation phase after nerve injury, which is necessary for myelin clearance and subsequent remyelination (23). Moreover, the PI3K/Akt and ERK/MAPK signaling pathways have been implicated in various aspects of neuron survival and axonal regrowth. These pathways not only support neuronal health but also influence the behavior of Schwann cells and macrophages, thereby modulating the immune environment conducive to regeneration (24).

Upon PNI, Wallerian degeneration ensues progressively within the first week post-injury. During this period, Schwann cells and damaged axons release soluble factors that activate resident macrophages and attract blood-derived macrophages to the injury sites. In the initial stages following nerve damage, macrophages are swiftly recruited and predominantly exhibit a pro-inflammatory M1 phenotype. These M1 macrophages secrete a range of pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-1 (IL-6), and are involved in the phagocytosis and degradation of myelin debris and necrotic cells. This process is crucial for clearing the injury site, mitigating the inflammatory response, and creating a favorable microenvironment for subsequent regeneration processes (25). Following the clearance of the injury site and the attenuation of the inflammatory response, macrophages progressively shift toward an anti-inflammatory M2 phenotype (26). M2 macrophages release a range of anti-inflammatory cytokines and growth factors, including interleukin-10 (IL-10), transforming growth factor beta (TGF-β), and insulin-like growth factor-1 (IGF-1), which facilitate tissue repair, extracellular matrix reconstruction, and the promotion of nerve regeneration (27). Throughout the nerve regeneration process, macrophages modulate the local immune milieu by interacting with other immune cells, such as T cells and B cells, thereby maintaining a balance between pro-inflammatory and anti-inflammatory responses (28). Furthermore, macrophages interact with Schwann cells to synergistically promote axonal regeneration and myelin repair, as noted in previous studies (29). Therefore, the macrophage response is deemed essential for the regeneration of injured peripheral nerves.

Neutrophils, another class of immune cells, rapidly infiltrate the site during the initial phases of nerve injury. They are functional in clearing cellular debris through phagocytosis and contribute to tissue degradation and clearance by releasing a variety of enzymes and reactive oxygen species (ROS). Nonetheless, an excessive accumulation of neutrophils can provoke an overwhelming inflammatory response, potentially leading to detrimental effects (30).

Following nerve injury, neutrophils are among the first immune cells to be recruited to the site of injury. Their rapid arrival is assisted by chemotactic factors, including CXCL1 and CXCL2 (31). Neutrophils release a variety of factors, such as cytokines (e.g., TNF-α, IL-1β, IL-6) and chemokines (e.g., MIP-2) (32), which serve to attract and activate additional immune cells, including macrophages and T cells (33). At the injury sites, the primary role of neutrophils is to clear cellular debris and pathogens through the process of phagocytosis. They degrade and digest cellular debris and pathogens through the release of ROS and enzymes, such as myeloperoxidase (34), thereby facilitating the clearance of the injury site and establishing a conducive environment for subsequent regenerative processes.

Although the primary role of neutrophils is to clear debris and prevent infection, but their activity can also lead to unintended consequences that impede nerve regeneration. One of the adverse effects of neutrophils is their ability to release neutrophil extracellular traps (NETs), which can delay the repair process in Wallerian degeneration by inhibiting macrophage infiltration into the parenchyma. This inhibition is harmful because macrophages play a significant role in clearing myelin debris and facilitating nerve regeneration. The formation of NETs outside the parenchyma acts as a barrier, preventing the necessary macrophage activity that supports nerve repair (33). In addition, neutrophils can release toxic soluble factors, such as matrix metalloproteinases, ROS and cytokines, which have neurotoxicity and thereby aggravate the peripheral injury (35).

T cells are also integral to the repair of peripheral nerve injuries. Research indicates that T cells are involved in the inflammatory response following nerve injury, which can either enhance or impede regeneration, contingent upon their subtype and the local microenvironment. For example, CD4⁺ T cells and CD8⁺ T cells infiltrate the damaged area. CD4⁺ T cells modulate macrophage polarization and function through the secretion of cytokines, including IL-4 and IL-10, thereby promoting nerve regeneration (15). Conversely, CD8⁺ T cells contribute to the maintenance of tissue integrity by eliminating infected or injured cells in the damaged area via cytotoxic mechanisms (36). Regulatory T (Treg) cells have been identified as pivotal in mitigating neuropathic pain by suppressing the Th1 response at the site of injury (15). This indicates that Treg cells may enhance the environment for nerve regeneration by modulating the immune response.

The presence of activated T cells has also been linked to adverse effects on nerve repair. Empirical evidence suggests that a deficiency in T cells may facilitate enhanced functional recovery post-PNI, as demonstrated in studies utilizing RAG2^-/- mice, which are devoid of mature T and B lymphocytes (37). These findings underscore the possibility that T cells may impede motor recovery following nerve injury, indicating that their accumulation could be detrimental in certain contexts. Additionally, the accumulation of T cells within acellular nerve allografts has been shown to be length-dependent, affecting the regenerative capacity of these grafts (38). This indicates that the spatial and temporal dynamics of T cell infiltration are important factors that can dictate the success of nerve repair strategies.

While traditionally, macrophages and Schwann cells have been the primary focus in studies of PNR, recent findings suggest that B cells also play a significant role in this process. B cells are known for their functions in antibody production and immune regulation, but they may also contribute to nerve repair through the secretion of neurotrophic factors and cytokines that can influence the behavior of other cells involved in regeneration. After PNI, B cells secrete antibodies and cytokines to eliminate pathogens and debris at the injury site, participate in regulating local inflammatory responses, and thereby create a more favorable microenvironment for nerve regeneration (37). B cells can be activated and migrate to the injury site, where they may help modulate the inflammatory response. This modulation is crucial, as inflammation can either promote or inhibit nerve regeneration depending on its nature and timing (39). For instance, a balanced immune response involving both pro-inflammatory and anti-inflammatory signals is necessary for optimal nerve healing (40).

Moreover, the interaction between B cells and Schwann cells may also facilitate nerve regeneration. Schwann cells can respond to signals from B cells, potentially influencing their proliferation and differentiation, which are critical for effective nerve repair (41). In addition, the genetic features of young and aged animals after PNI suggest that the immune response, including B cell activation, varies significantly with age, impacting the overall regeneration capacity (42). Understanding the specific mechanisms by which B cells influence PNR could lead to novel therapeutic strategies aimed at enhancing recovery after nerve injuries.

Following PNI, natural killer (NK) cells have been shown to infiltrate the injured site and exert significant effects on the regeneration process. They regulate the local inflammatory response by secreting cytokines (such as Interferon-gamma (IFN-γ), and TNF-α) and chemokines. These cytokines can activate other immune cells, such as macrophages and T cells, thereby forming a coordinated immune response. This enhances the phagocytic activity and antigen-presenting ability of macrophages, thereby improving the response of T cells and aiding in the clearance of debris and pathogens at the injury site (43). It has been demonstrated that NK cells can selectively induce the degeneration of damaged sensory axons through the re-expression of specific ligands in dorsal root ganglion neurons, which triggers their cytotoxic activity (44). This process is crucial as it complements the natural Wallerian degeneration, facilitating the clearance of damaged axons and potentially enhancing the regenerative environment for intact axons.

Dendritic cells play a crucial role in the immune response and have been increasingly recognized for their involvement in PNI and PNR. They initiate and regulate the initial immune response by recognizing and ingesting antigens from damaged cells and pathogens. Activated dendritic cells secrete various cytokines and chemokines (such as IL-12 and TNF-α) at the injury site, attracting other immune cells such as macrophages and T cells to the site, thereby enhancing the local immune response (45). Dendritic cells are the most effective antigen-presenting cells in the body. They present the ingested antigens to T cells through MHC class I and MHC class II molecules, thereby activating T cells. In this way, dendritic cells play a bridging role in the regeneration process after neural injury, converting the innate immune response into a specific adaptive immune response (46). Dendritic cells can not only activate pro-inflammatory T cells (such as Th1 and Th17), but also regulate the activity of anti-inflammatory T cells (such as Treg cells) by secreting anti-inflammatory cytokines (such as IL-10 and TGF-β) (43). This dual regulatory role helps balance the local immune response, protecting neural tissue from excessive inflammatory damage while promoting the formation of a regenerative environment.

Toll-like receptor (TLR) signaling is integral to the orchestration of innate immune responses, facilitating the efficient and rapid removal of inhibitory myelin debris and thereby enhancing PNR (47). The initial expression of interleukin-1β and monocyte chemoattractant protein-1 in the distal stump of the sciatic nerve is impaired in mice with defects in TLR signaling transduction. Conversely, animals administered a single microinjection of TLR2 and TLR4 ligands at the site of sciatic nerve injury demonstrated an accelerated clearance of degenerated myelin sheaths and a reduced recovery period compared to control rats (47). TLRs are activated following PNI, promoting an inflammatory response. Specifically, TLR4 induces the production of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, by activating the nuclear factor kappa B (NF-κB) and MAPK signaling pathways. These cytokines play a pivotal role in the early inflammatory response, aiding in the clearance of cellular debris and pathogens from the injury sites (48).

The NLRP3 inflammasome is activated following PNI, promoting the maturation and release of IL-1β and IL-18 (49). These cytokines play a role in the nerve regeneration process by regulating the inflammatory response and promoting the survival and growth of nerve cells. Studies have shown that Berberine significantly downregulates the expression of the NLRP3 inflammasome and its related molecules in macrophages, thereby alleviating macrophage M1 polarization and inflammation induced by NLRP3 inflammasome activation (50). Consequently, the neuroprotective effects of Berberine are concomitant with the suppression of inflammation following PNI, primarily through the inhibition of macrophage M1 polarization induced by NLRP3 inflammasome activation (50).

PNI elicits distinct expression profiles of growth factors and cytokines, which play a crucial role in modulating the response to injury and facilitating regeneration, through specific intracellular signaling pathways. For instance, the JAK/STAT signaling pathway mediates signal transduction via the GP130 receptor complex, with the activation of signal transducer and activator of transcription (STAT3) being pivotal in modulating the immune cell response at the site of injury (51). PNI also stimulates the production of IL-6-related neurotrophic cytokines, which contribute to neuroprotection and regeneration via the STAT pathway, which is locally activated in damaged nerves (52).

The PI3K/Akt signaling pathway is activated by growth factors, including NGF and BDNF, thereby promoting neuronal survival and axonal regeneration. This pathway is essential in regulating cellular growth, proliferation, and survival. Studies have demonstrated that the administration of exogenous glial cell line-derived neurotrophic factor into the buccinator muscle enhances the expression of growth-associated protein 43 and confers neuroprotection to facial neurons via the PI3K/Akt/mTOR signaling cascade. This intervention enhances the regeneration of facial nerves post-crush injury and aids in the restoration of neural conduction function (53). Another study demonstrated that CXCL12 expression was elevated during the initial stages of facial nerve injury and diminishes after two weeks. CXCL12 markedly enhanced Schwann cell migration, decreased the phosphorylation of PI3K, AKT, and mTOR, and elevated the expression of the autophagy marker LC3 II/I. In the animal study, CXCL12 was found to improve facial nerve function and promote myelin regeneration, suggesting its potential as a key therapeutic target (54).

NF-κB signaling pathway plays a pivotal role in regulating the immune system and has significant implications for PNR. It is crucial for the expression of various pro-inflammatory cytokines and mediators that are involved in immune responses. Aberrant activation of NF-κB has been linked to several pathological conditions, including autoimmune diseases and neurodegenerative disorders, which can adversely affect nerve regeneration (55, 56).

In PNI, NF-κB signaling is activated in response to inflammatory stimuli, leading to the production of cytokines such as TNF-α and IL-1β, which can exacerbate neuropathic pain and hinder regeneration (57). Studies have shown that inhibiting NF-κB activity can alleviate pain and improve functional recovery following nerve injuries, suggesting that targeting this pathway may enhance nerve regeneration (58, 59). Moreover, another research indicates that immune modulation through NF-κB signaling can influence the behavior of glial cells in the spinal cord, which are critical for maintaining homeostasis and supporting neuronal health during the regeneration process (60). The interplay between NF-κB and various signaling pathways, including those involving macrophage polarization, further underscores its importance in orchestrating the regenerative response following PNI (61).

Notch signaling has emerged as a critical pathway in the regulation of various biological processes, including immune responses and tissue regeneration. Notch signaling has been shown to influence macrophage polarization, thereby affecting their role in nerve repair (62). During the axonal injury regeneration process, there is a marked increase in the number of autophagic vesicles. The activation of autophagy facilitates the expedited clearance of myelin debris and enhances the repair process. Previous studies have demonstrated that DLK-mediated injury signaling can activate autophagy, which may subsequently limit the levels of LIN-12 and Notch proteins, thereby promoting axonal regeneration (63). Furthermore, it is well established that dedifferentiated Schwann cells are crucial for neural regeneration, and Notch signaling plays a significant role in activating the proliferation and differentiation of Schwann cells, effectively promoting neural repair in the early regeneration stage (64).

The complement system plays an important role in the injury and regeneration of the PNS. Complement not only participates in the clearance of pathogens and the regulation of inflammatory response, but also plays a key role in the repair process after nerve injury. Studies have shown that complement components are activated after PNI and promote nerve regeneration by regulating the function and migration of immune cells (65). The signaling of complement C3 was found to be essential for skeletal muscle regeneration, a process that involves the function and migration of monocytes (65). Some components of the complement system, such as C1q and C3, have been shown to promote axonal regeneration of retinal ganglion cells after optic nerve injury. These complement components promote the cleaning of the injury site and the establishment of a regenerative environment through the interaction with microglia and monocytes (66). In treating PNI, the regulation of the complement system may provide opportunities for the development of new therapeutic strategies. For example, treatment targeting the complement system can help improve the effect of nerve regeneration, especially in the case of severe injury (67). By regulating the activity of complement, it may enhance the regeneration ability of Schwann cells, thus promoting the functional recovery of nerves (68).

Cytokines are small protein messengers that serve as critical mediators in various physiological and pathological processes. They are secreted by one cell and can act autocrinely on the same cell or paracrinely on other cells. They play a pivotal role in the immune response, acting as signaling molecules that facilitate communication between cells. Concurrently, they play a role in the pathogenesis of inflammation associated with various diseases (69). Currently, biologic agents targeting cytokines are extensively utilized in therapeutic interventions for tumors, autoimmune diseases, immune deficiencies, infections and other aspects.