The inflammatory cascade following peripheral nerve injury is initiated by the immediate release of Damage-Associated Molecular Patterns (DAMPs) from ruptured axons, degenerating myelin, and compromised Schwann cells (Lin et al., 2025). These endogenous “danger signals,” which include molecules like high-mobility group box 1 (HMGB1), heat shock proteins (HSPs), ATP, and DNA fragments, are recognized by pattern recognition receptors (PRRs) - such as Toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE) - expressed on resident immune cells (e.g., endometrial macrophages) and Schwann cells themselves (Ramadan et al., 2017). This DAMP-PRR interaction serves as the critical “alarm signal,” triggering the activation of key transcription factors like nuclear factor kappa-B (NF-κB) and activator protein 1 (AP-1). Subsequently, this leads to the rapid production and secretion of pro-inflammatory cytokines and chemokines (Rubartelli and Lotze, 2007). The resulting chemokine gradient is responsible for the precise spatiotemporal recruitment of circulating neutrophils and monocytes to the injury site, marking the transition from a sterile insult to an active immune response. Thus, DAMP-mediated signaling is not merely a bystander effect of injury; it is the fundamental mechanism that orchestrates the initial immune cell infiltration, setting the stage for the subsequent dual-phase (destructive and constructive) roles of inflammation in nerve repair.

During the initial phase of peripheral nerve injury, a well-modulated inflammatory response serves as a critical driver for initiating and ensuring successful regeneration. At this stage, inflammation first performs a debridement function: neutrophils and macrophages that rapidly infiltrate the injury site clear necrotic tissue along with degenerated axonal and myelin debris through efficient phagocytosis, thereby creating a pristine microenvironment for subsequent axonal regeneration (Jin et al., 2012). Subsequently, inflammatory signals initiate the repair program: pro-inflammatory cytokines such as TNF-α and IL-1β, released by immune cells, activate signaling pathways including NF-κB within Schwann cells, driving their phenotypic switch-from a mature myelin-maintaining state to an active repair state through dedifferentiation (Guo et al., 2024). This transition is characterized by the downregulation of myelin-associated genes and the upregulation of repair-related genes such as c-Jun and glial cell line-derived neurotrophic factor (GDNF), prompting Schwann cells to proliferate and align into critical structures known as Bands of Büngner, which guide directional axonal extension (Li et al., 2019; McAlhany et al., 2000; Sangaraju et al., 2019; Vaudano et al., 2001). Notably, under specific conditions and at low concentrations during the early injury phase, cytokines like IL-1β and IL-6 can directly promote Schwann cell proliferation and enhance their ability to synthesize and secrete neurotrophic factors such as nerve growth factor (NGF), exerting beneficial neuroprotective and pro-regenerative effects in the short term (Chen et al., 2016; Zhou et al., 2020). Furthermore, to meet the high energy demands of the regeneration process, vascular endothelial growth factor (VEGF) secreted by macrophages and fibroblast growth factor-2 (FGF-2) synergize with angiopoietin-1 released by Schwann cells to effectively promote neovascularization at the injury site (Duobles et al., 2008; Ganta et al., 2019; Huang et al., 2014). This nascent vascular network supplies essential oxygen and glucose to regenerating neurons and Schwann cells, thereby providing robust metabolic support for nerve regeneration (Keilhoff et al., 2008; Tang et al., 2023).

When the inflammatory response becomes uncontrolled or transitions from acute to chronic, its nature shifts from constructive to destructive, severely impeding the repair and regeneration of peripheral nerves through multiple interconnected mechanisms (Cobo et al., 2018; Nguyen et al., 2023; Vanucci-Bacqué and Bedos-Belval, 2021). First, the persistent inflammatory microenvironment exerts direct neurotoxicity (Cao et al., 2024). Sustained high levels of TNF-α engage the TNF Receptor 1 (TNFR1) on neurons, leading to the assembly of the caspase-8 activating complex (DISC), which initiates the extrinsic apoptotic cascade. Similarly, IL-1β can impair mitochondrial function, promoting cytochrome c release and activation of the intrinsic caspase-9 apoptotic pathway (Ng et al., 2018; Tylutka et al., 2024; Wang and He, 2018; Kim et al., 2004; Trichonas et al., 2010; Beckham et al., 2010; Hu et al., 2019). Second, a severe imbalance occurs in the regulation of immune cells, which is central to the repair process (Hua et al., 2019; Li et al., 2022). The sustained polarization of macrophages towards the pro-inflammatory M1 phenotype results in excessive secretion of detrimental factors like IL-6, TNF-α, and matrix metalloproteinase-9 (MMP-9) (Davis et al., 2018; Han et al., 2025). This not only suppresses the reparative functions of Schwann cells but also disrupts the structure of the Büngner bands (Roet et al., 2014), which are essential for guiding axonal growth. Concurrently, the anti-inflammatory and pro-repair M2 macrophage phenotype is suppressed, preventing the timely resolution of inflammation and creating a vicious cycle (Li P. et al., 2024; Lopes et al., 2024; McKenzie et al., 2006). Third, dysregulated inflammation drives detrimental tissue remodeling (Antonangeli et al., 2020). Excessive activation of fibroblasts, driven by factors like TGF-β1 (Montero et al., 2021), leads to the production of abundant collagen fibers and inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) (Li et al., 2021; Zhang et al., 2024). The CSPGs in the scar tissue primarily exert their inhibitory effect by binding to the Protein Tyrosine Phosphatase Sigma (PTPσ) receptor on growth cones. This interaction leads to the inactivation of integrin signaling and, most critically, the activation of the small GTPase RhoA and its effector ROCK (Rho-associated kinase). RhoA/ROCK activation then drives actomyosin contraction, causing growth cone collapse and halting axonal advancement (Jessen et al., 2015; Joosten et al., 2000; Li et al., 2015). It is noteworthy that endogenous compensatory mechanisms exist to counteract this inhibitory signaling. For instance, neurons can upregulate receptors like the LAR family phosphatases, which may compete for CSPG binding (Xu et al., 2015), or activate counteracting pathways via neurotrophic factors (e.g., BDNF, GDNF) (Cornejo et al., 2021). These factors can signal through PI3K/Akt to inhibit RhoA activity and promote the activity of growth-promoting GTPases like Rac1 and Cdc42. However, in a chronic inflammatory milieu characteristic of conditions like diabetic neuropathy, these protective pathways are often suppressed or overwhelmed, allowing the inhibitory CSPG-RhoA/ROCK axis to dominate and contributing to regenerative failure. Furthermore, chronic inflammation impairs the crucial neurotrophic support system (Gurnani et al., 2025). On one hand, it downregulates the ability of Schwann cells to synthesize neurotrophic factors like Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) (Meyer et al., 1992). On the other hand, it causes desensitization of the corresponding receptors on neuronal surfaces (Zhang et al., 2009). Consequently, regenerating neurons are deprived of external trophic support and become unable to effectively respond to these supportive signals (Masson and Nait-Oumesmar, 2023; Titz et al., 2003), plunging them into a state of “starvation” and increasing their risk of apoptosis (Fan et al., 2021; Previtali, 2021). Finally, inflammation disrupts the structural foundation maintaining the neural internal environment. Overproduction of factors like Vascular Endothelial Growth Factor (VEGF) increases the permeability of the blood-nerve barrier, leading to substantial infiltration of inflammatory cells from the vasculature and accumulation of inflammatory exudates. This causes local edema, which compresses nerve fibers and further deteriorates the already vulnerable regenerative microenvironment (Suter et al., 1993; Wu et al., 2022).

In summary, inflammation plays a spatiotemporally dependent dual role in peripheral nerve regeneration, and its precise regulation is pivotal to the success of regeneration. As illustrated in Figure 1 above, this “double-edged sword” effect persists throughout the entire process.

An appropriate degree of inflammation is an essential component of functional recovery following neural injury (Munro et al., 2012). However, excessive inflammation leads to persistent activation of immune cells and degeneration of neural cells (Gao et al., 2022; Zhang et al., 2010). Spatiotemporal modulation of M1/M2 macrophage polarization can reshape the local inflammatory immune microenvironment, steering it toward a state conducive to tissue repair (Van den Bossche et al., 2016). Following peripheral nerve injury, macrophages precisely regulate the regenerative microenvironment through the secretion of various factors (Gu et al., 2024; Li X. et al., 2024; Wang JY. et al., 2024). Macrophages precisely regulate the regenerative microenvironment through secreted factors that activate specific cellular programs. For instance, macrophage-derived IL-6 binds to the IL-6 receptor on Schwann cells, activating the intracellular JAK/STAT3 signaling pathway. This phosphorylation cascade directly translocates to the nucleus to upregulate genes such as Cyclin D1, thereby driving Schwann cell cycle entry and proliferation (Leibinger et al., 2016). Conversely, TGF-β secreted by reparative macrophages primarily signals through the Smad2/3 pathway in fibroblasts and Schwann cells. This activation leads to the transcription of genes encoding extracellular matrix (ECM) components like collagen I and fibronectin, but crucially, in a regulated manner that promotes healthy ECM remodeling rather than dense fibrotic scarring (Huang et al., 2024). Furthermore, IGF-1 exerts its pro-regenerative effects by binding to the IGF-1 receptor on neurons, which activates the PI3K/Akt/mTOR survival pathway, inhibiting apoptosis and promoting axonal outgrowth. Research utilizing electrospinning techniques has constructed a multifunctional, multi-layered nanofiber composite membrane from polycaprolactone (PCL) and amniotic membrane (AM) (Xue et al., 2019). In vitro studies demonstrate that the PCL/AM composite promotes axonal growth in SH-SY5Y cells and induces their differentiation into neurons (Liu et al., 2023). When used to wrap nerve stumps, the PCL/AM composite creates a microenvironment favorable for nerve regeneration by blocking the invasion of scar tissue, promoting macrophage recruitment and their moderate polarization toward the M2 phenotype (Lu et al., 2024). This process enhances the expression of anti-inflammatory cytokines IL-10 and IL-13 while suppressing the expression of pro-inflammatory cytokines IL-6 and TNF-α, ultimately inducing myelination and axonal regeneration (Abidi et al., 2022). By releasing various bioactive substances that modulate M2 macrophage polarization and the formation of anti-inflammatory factors, the PCL/AM complex can enhance axonal regeneration and improve neurological repair (Wang et al., 2019).

Under physiological conditions, Schwann cells in the peripheral nerve exist primarily in two functional subtypes: myelinating Schwann cells, which ensheath large-diameter axons to form the myelin sheath, and non-myelinating Remak Schwann cells, which envelop multiple small-diameter axons. Following peripheral nerve injury, both subtypes undergo a process of dedifferentiation, downregulating myelin-maintaining genes (e.g., MPZ, PMP22) and upregulating a repair-specific program. This transforms them into a plastic, proliferative “repair” phenotype. Inflammatory signals following peripheral nerve injury serve as the key initiating factor driving the phenotypic switch of Schwann cells from a myelinating state to a repair state (Jiang et al., 2025). Pro-inflammatory cytokines such as TNF-α and IL-1β activate pathways like NF-κB, which downregulate the expression of myelin-associated genes (e.g., MPZ, PMP22) in Schwann cells while upregulating repair-related genes (e.g., c-Jun, GDNF) (Huang et al., 2015). This dedifferentiation enables Schwann cells to proliferate extensively and align into critical structures called Büngner bands, which guide axonal regeneration (Schuh et al., 2016). These cells also secrete extracellular matrix components such as laminin and fibronectin, providing essential “tracks” and support for regenerating axons.

Activated Schwann cells further contribute by secreting neurotrophic factors like NGF and BDNF, which activate the PI3K/Akt survival pathway in neurons, alongside releasing GDNF, which is crucial for motor neuron regeneration (Bierlein De la Rosa et al., 2017). Together, these actions form a favorable intercellular signaling network that supports regeneration. However, this repair process operates within a critical time window; persistent or excessive inflammatory signals can lead to Schwann cell senescence or tissue fibrosis, ultimately impeding nerve regeneration (Cutolo et al., 2022).

Peripheral nerve injury and disease often lead to persistent pain that continues after the initial injury has subsided, indicating an active disease process that may result in chronic pain conditions (Sommer et al., 2018). While well-controlled neuroinflammation can promote regeneration and healing, impaired resolution of neuroinflammation can lead to chronic pain (Subhramanyam et al., 2019). Research over the past decades has accumulated substantial knowledge about these physiological and pathophysiological processes and identified potential therapeutic targets (Bishop et al., 2021). Key participants in inflammatory processes include macrophages, T lymphocytes, cytokines, and chemokines (Cassol et al., 2015). Within the spinal cord and brain, microglia and astrocytes actively contribute to disease progression. MicroRNAs and other non-coding RNAs have been identified as potential key mediators linking neural injury, pain, and inflammation (Daidone et al., 2021). Among the clinical conditions most extensively studied in the context of neuroinflammation and pain are complex regional pain syndrome, polyneuropathy, postherpetic neuralgia, and fibromyalgia syndrome (Sommer et al., 2018; Wen et al., 2023). Studies from several research groups have demonstrated that both pro-inflammatory and anti-inflammatory cytokines play significant roles in human neuropathic and other chronic pain states. Substantial evidence indicates that anti-inflammatory cytokines exert analgesic effects in animal models (Herrerias et al., 2009). The interaction between anti-inflammatory cytokines and the nociceptive system presents both opportunities and challenges for therapeutic development.

After animal models clearly demonstrated the critical role of cytokine-mediated neuroimmune responses in pain, research focus naturally shifted toward clinical validation. However, establishing a specific link between cytokines and pain symptoms in patients with neuropathy has proven far more challenging than anticipated. Early studies targeting circulating cytokines initially appeared to support the “pain susceptibility” cytokine profile hypothesis. A prospective study found that compared to patients with painless neuropathy and healthy controls, patients with painful neuropathy exhibited significantly elevated mRNA and protein levels of pro-inflammatory cytokines (e.g., IL-2, TNF-α) in their blood, while painless patients showed a predominant upregulation of the anti-inflammatory cytokine IL-10 (Table 1) (Baka et al., 2021). Notably, this difference was independent of the etiology of the neuropathy (e.g., whether it was an inflammatory neuropathy), suggesting the potential existence of a cross-disease, endogenously determined immune imbalance state that predisposes individuals to pain susceptibility (Meacham et al., 2017). A similar trend was partially corroborated in studies on painful diabetic neuropathy (Zhang et al., 2021). Nonetheless, the results from these blood-based studies have been inconsistent, potentially limited by patient cohort heterogeneity, sample size, and variations in detection methodologies.

To more precisely elucidate pain mechanisms, subsequent studies shifted to direct analysis of affected sural nerve and skin samples. However, the results were unexpected: local tissue cytokine changes proved far more complex than those in blood (Kong et al., 2022). More importantly, the severity of neuropathic pain showed no direct correlation with the extent of T-cell or macrophage infiltration in nerve or skin tissues. These negative findings suggest that neuropathic pain may not be simply determined by the absolute levels of a few cytokines, but rather stems from dysregulation within a more intricate and dynamic network of local cellular interactions (Baron et al., 2010). A key insight is that neuropathy involves extensive alterations in cutaneous gene expression, indicating that pain maintenance may rely on sustained interactions between nerve endings and non-neuronal cells (e.g., keratinocytes, immune cells) within the skin (Kreß et al., 2021).

As illustrated in Figure 2, under the pathological conditions of diabetic peripheral neuropathy (DPN), this precisely orchestrated repair program is severely disrupted by the chronic inflammatory microenvironment resulting from persistent hyperglycemia (Greten and Grivennikov, 2019; Stone et al., 2017). Prolonged metabolic dysregulation constitutively activates canonical inflammatory signaling pathways, such as nuclear factor kappa-B (NF-κB), via pattern recognition receptors (e.g., Toll-like receptors) (Hilgendorf et al., 2024). This not only directly triggers neuronal axonal degeneration and myelin breakdown (Wallerian degeneration) but also leads to sustained high-level expression of pro-inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α), establishing a persistent inflammatory cascade that is difficult to resolve (Monk et al., 2015). These cytokines play a particularly complex dual role in DPN, with their effects being highly dependent on the specific spatiotemporal context and concentration. On one hand, they exacerbate neural damage, insulin resistance, and pathological pain through direct neurotoxicity (e.g., IL-1β inhibiting the PI3K/Akt neuronal survival pathway, TNF-α inducing apoptosis) and by indirectly activating glial cells to produce more inflammatory mediators (Hyung et al., 2018; Sugiura and Lin, 2011). On the other hand, under specific conditions, inflammatory signals are necessary for initiating repair; for instance, IL-1 has been shown to transiently promote Schwann cell proliferation and upregulate nerve growth factor (NGF) expression, suggesting its potential to switch from a damaging factor to a reparative signal (Hughes and Appel, 2016; Salzer, 2015). Once this delicate balance is disrupted by chronic inflammation, it ultimately compromises the neurotrophic factor system, which is vital for neuronal survival and functional maintenance.

Neurotrophic factors (e.g., NGF, NT-3) play a central role in maintaining neuronal soma health, guiding directional axonal growth, and promoting myelination (Ricci et al., 2024). In the DPN state, the chronic inflammatory microenvironment can lead to significant downregulation of neurotrophic factors and their receptors, severely impairing their anti-apoptotic, pro-growth, and Schwann cell-supporting functions, thereby fundamentally constraining effective nerve regeneration and repair (Peng et al., 2023).

In summary, the pathogenesis of DPN can be viewed as a vicious cycle network comprising three interconnected components: vascular support dysfunction, immune-inflammatory imbalance, and neurotrophic failure. A deep understanding of the spatiotemporal dynamics and interactions of the various factors within this network is crucial for developing breakthrough therapeutic strategies.

Beyond endogenous immune regulatory mechanisms, exogenous pharmacological interventions have emerged as a potential strategy for promoting nerve regeneration. A central therapeutic strategy is to shift the balance from pro-inflammatory M1 to pro-reparative M2 macrophages. This can be achieved by targeting key regulatory hubs. The NLRP3 inflammasome is a critical driver of M1 polarization. The natural alkaloid berberine (BBR) has been shown to promote functional recovery in a sciatic nerve injury model by directly inhibiting NLRP3 activation and IL-1β maturation (Godai and Moriyama, 2022; Wang J. et al., 2024). This inhibition skews macrophages towards an M2 phenotype, characterized by increased expression of Arg1 and IL-10, creating a microenvironment conducive to Schwann cell-mediated repair (Chew et al., 2013; Elsayed et al., 2020). Similarly, the diabetes drug metformin exerts immunomodulatory effects via activation of AMP-activated protein kinase (AMPK), which inhibits the NF-κB pathway and promotes M2 marker expression (Postler et al., 2021). Table 2 lists several common nerve repair drugs.

Another approach is to dismantle the inhibitory barriers to regeneration. CSPGs in the glial scar activate the growth cone-collapsing RhoA/ROCK pathway. The ROCK inhibitor fasudil has demonstrated efficacy in nerve injury models by not only reducing this CSPG-mediated inhibition but also by decreasing neutrophil infiltration and promoting M2 macrophage polarization, thereby acting on both the chemical and cellular barriers to regeneration (Ouyang et al., 2024).

Based on an in-depth understanding of the inflammatory and immune mechanisms underlying neuropathy, therapeutic strategies targeting these processes have become a research focus. Among them, Traditional Chinese Medicine (TCM) compounds exhibit unique potential due to their multi-component, multi-target characteristics (Yang et al., 2025). Taking the JinMaiTong (JMT) compound, used for treating DPN, as an example, its formulation follows the TCM principles of “tonifying the kidney, activating blood circulation, warming the tendons, and unblocking the collaterals,” targeting the core pathogenesis of DPN identified in TCM as “kidney deficiency and blood stasis” (Bai et al., 2021). Clinical studies have preliminarily confirmed its ability to improve symptoms and nerve conduction velocity in DPN patients (Hu et al., 2025).

To elucidate its scientific basis, a series of fundamental studies have been conducted from the whole-animal level down to the cellular level. Research indicates that JMT not only ameliorates glucolipid metabolism and reduces oxidative stress and apoptosis but also upregulates the expression of neurotrophic factors (such as NGF and CNTF) in the sciatic nerve (Maisonpierre et al., 1990; Yin et al., 2015). Most importantly, subsequent research has further focused on inflammatory pathways. Utilizing modern molecular biology techniques, it has been confirmed that JMT likely alleviates inflammatory damage in nerve tissue, promotes Schwann cell proliferation, and enhances their neurotrophic function by regulating key signaling pathways such as NF-κB. Consequently, it exerts a synergistic effect promoting nerve repair and regeneration through multiple targets and pathways (Molina-Gonzalez et al., 2023). The research paradigm established by JMT provides valuable clues for discovering drugs that treat peripheral neuropathy through immune regulation from the repository of traditional medicine. It is important to note that while preclinical studies and preliminary clinical trials of several months’ duration support the safety and efficacy of JMT for DPN, comprehensive long-term toxicological and pharmacokinetic data from large-scale, multi-year human studies are still limited. Future research adhering to modern drug development standards is needed to fully establish its long-term safety profile and optimal dosing regimens, which is a crucial step for its broader clinical translation and acceptance.

Beyond pharmacological agents, cellular therapies have emerged as a potent strategy to directly deliver or instruct immunomodulatory cells to the injury site, offering a dynamic approach to reshape the regenerative microenvironment (Petrus-Reurer et al., 2021). The core principle is to leverage the innate abilities of certain cell types to modulate macrophage polarization from a pro-inflammatory (M1) to an anti-inflammatory, pro-regenerative (M2) phenotype, thereby resolving chronic inflammation and creating a conducive environment for repair.

Among the most extensively investigated candidates are mesenchymal stem/stromal cells (MSCs). Transplanted MSCs secrete a wide array of bioactive factors—such as PGE2, TGF-β, and IL-10-that collectively suppress pro-inflammatory M1 macrophage activation while promoting their polarization toward an M2 phenotype (Liu et al., 2019). This shift is crucial for dampening chronic inflammation, reducing fibrosis, and enhancing Schwann cell-mediated repair and axonal regeneration. The efficacy of this approach is not limited to direct cell-cell contact; MSC-conditioned media (MSC-CM), containing the paracrine secretome of these cells, has been shown to significantly inhibit the expression of pro-inflammatory mediators (e.g., iNOS, COX-2, IL-1β, IL-6) in macrophages by suppressing key signaling pathways like NF-κB and MAPK (Chang et al., 2021). Furthermore, a novel and sophisticated evolution of this concept involves using MSC-derived extracellular vesicles (MSC-EVs). These vesicles encapsulate therapeutic cargo (e.g., miRNAs, proteins) and can efficiently deliver it to target cells, including macrophages, to instruct an M2-polarized state. MSC-EVs offer advantages over whole-cell therapies, including reduced risks of tumorigenicity and immunogenicity, and easier storage and standardization.

Other innovative strategies involve the direct administration of pre-polarized immune cells. This includes the transfusion of ex vivo-generated regulatory macrophages (M2-like) or the modulation of regulatory T cells, which can subsequently influence endogenous macrophage populations at the injury site towards a reparative phenotype (Cai et al., 2021). These approaches aim to “reset” the local immune landscape more rapidly and precisely than systemic drug administration.

The future of cellular therapy lies in combination and bioengineering strategies. This includes integrating MSCs or engineered macrophages within biomaterial scaffolds that provide structural guidance and controlled release of supportive factors, or creating “smart” cells via gene editing to respond to specific inflammatory cues within the nerve lesion. While challenges related to cell source, survival, delivery, and precise control of function remain, cellular therapies represent a paradigm shift towards leveraging the body’s own regulatory systems for precise, multifaceted immune modulation in nerve repair.