The Role of Cytokines in Postherpetic Neuralgia

Abstract

Nerve injury is a significant cause of postherpetic neuralgia (PHN). It is marked by upregulated expression of cytokines secreted by immune cells such as tumor necrosis factor alpha, interleukin 1 beta (IL-1β), IL-6, IL-18, and IL-10. In neuropathic pain (NP) due to nerve injury, cytokines are important for the induction of neuroinflammation, activation of glial cells, and expression of cation channels. The release of chemokines due to nerve injury promotes immune cell infiltration, recruiting inflammatory cytokines and further amplifying the inflammatory response. The resulting disequilibrium in neuroimmune response and neuroinflammation leads to a reduction of nerve fibers, altered nerve excitability, and neuralgia. PHN is a typical NP and cytokines may induce PHN by promoting central and peripheral sensitization. Currently, treating PHN is challenging and research on the role of cytokine signaling pathways in PHN is lacking. This review summarizes the potential mechanisms of cytokine-mediated PHN and discusses the cytokine signaling pathways associated with the central and peripheral sensitization of PHN. By elucidating the mechanisms of cytokines, the cells and molecules that regulate cytokines, and their signaling systems in PHN, this review reveals important research developments regarding cytokines and their signaling pathways mediating PHN, highlighting new targets of action for the development of analgesic drugs.

Graphical abstract

Keywords

cytokine / neuropathic pain / postherpetic neuralgia / neuroimmune

1. Introduction

Neuropathic pain (NP) is a prevalent condition, affecting approximately 10.3% of individuals in the general population. Its incidence is notably higher in specific populations such as elderly patients with herpes zoster (HZ), patients with diabetes, and patients with cancer [1]. Studies indicated that 5–30% of HZ patients develop postherpetic neuralgia (PHN) [2], with more than 30% of these patients experiencing persistent neuralgia for more than 1 year. This chronic NP significantly reduces the quality of life, leading to sleep disorders, anxiety, depression, decreased physical function, and even debilitation [3]. Furthermore, it increases the economic burden on patients [4]. Consequently, PHN has become one of the most common chronic diseases affecting the quality of life and mental health of the elderly.

Indeed, a widely recognized contributor to NP is nerve injury. Neurons, the functional units of the nervous system, are capable of sensing stimuli, transmitting excitation, and activating corresponding brain regions to produce sensations. PHN, a typical form of NP associated with nerve injury, is also related to aging, immune deficiency, and genetic factors [5, 6, 7]. Nerve injury promotes the upregulation of inflammatory cytokines [8], activation of glial cells [9], and reduction of peripheral sensory nerve fibers [10, 11]. Subsequently, the abnormal expression of various ion channels related to pain signaling pathways in neurons leads to central sensitization, which is the primary cause of increased neuronal excitability and NP [12, 13, 14, 15]. However, although most adults infected with the varicella-zoster virus (VZV) experience some degree of nerve injury, not all HZ is accompanied by PHN, which might be a hint of the decline in immunity [16]. Therefore, events secondary to nerve injury, such as the release of chemokines by peripheral neuron cell bodies and Schwann cells, are likely to induce immune cell infiltration, further contributing to the development of NP [17, 18, 19]. From this perspective, nerve injury serves as the backdrop for the occurrence of PHN.

Although rodent models for exploring the pathogenesis of PHN, such as rat models induced by herpes simplex virus type 1 (HSV-1) and VZV, have been successfully constructed to the current time, there are differences in the pathways of PHN progression from viral latency to activated infection between these models and humans. Notably, so far, there have been no reports of constructed animal models that mimic the VZV reactivation process. Therefore, the development of a more reliable viral reactivation animal model that exhibits PHN-like herpetic pain is undoubtedly a major challenge we currently face. The pathogenesis of PHN is associated with nerve injury, and the generally accepted academic mechanism for the pathogenesis of PHN is central and peripheral sensitization, including abnormal activation of glial cells and dysfunction of ion channels. Meanwhile, although the pathogenesis of other NP may vary depending on their etiology, pathological processes such as nerve injury and abnormal ion channel function are always present. Given this, the study of other NP can undoubtedly provide a valuable reference for PHN. PHN, as a chronic neuralgia triggered by VZV invasion of nerves, is essentially, like all neuralgia, closely related to nerve injury, whether this injury is caused by viral infection, immune response, or mechanochemical factors. However, our study of the role of cytokines in PHN remains limited and clinical evidence seems insufficient due to the many challenges still facing the construction of current animal models of PHN. To fill this gap, we drew on other NP research findings to provide further insights into the pathogenesis of PHN when exploring the role of cytokines in PHN.

The pathogenesis of PHN remains under investigation. A growing body of evidence has enhanced our understanding of the role of inflammatory mediators, such as interleukins (ILs), tumor necrosis factor alpha (TNF-\alpha), ATP, and chemokines, in the mechanisms of NP [17, 20, 21, 22]. However, systematic and comprehensive studies on the changes and mechanisms of cytokines in the pathogenesis of PHN are still lacking. This paper reviews the peripheral and central mechanisms of PHN by which cytokines mediate pain, and also discusses the signaling pathways involved in its pathogenesis.In this paper, the identification of cytokines and neuroglial cells as potential therapeutic targets for PHN is emphasized, along with suggestions for future research avenues focusing on PHN treatment.

2. Nerve Injury

PHN is a prevalent type of NP in clinical practice and remains one of the most challenging chronic pain to manage. It is triggered by infection with VZV, a neurotropic herpes virus that lies dormant in human peripheral sensory ganglia. Reactivation of VZV is related to cellular immunity, which is typically effective in preventing such reactivation. However, compromised immune responses, especially in the elderly, facilitates VZV reactivation from dorsal root ganglia (DRG) latency, spreading along peripheral nerves to the skin [23, 24]. During viral replication, the immune system releases inflammatory mediators, including cytokines and chemokines [25]. This leads to inflammation, hemorrhagic necrosis, and neuronal loss in the affected DRG [26, 27], resulting in nerve damage. The inflammatory changes following nerve damage lead to the infiltration of immune cells, which are consistent with observations in other animal models of peripheral nerve injury [28, 29, 30, 31]. This causes spontaneous firing of peripheral neurons, lowered activation thresholds, and amplified incoming neural signals, manifesting as neuronal dysfunction and ectopic discharges [12, 13, 14, 25]. Interestingly, in the chronic constriction injury (CCI) model [32], thermal hyperalgesia can still occur when the ligature is loosely applied without causing actual mechanical damage. This suggests that the inflammatory response and the release of inflammatory mediators, rather than nerve injury itself, are key to maintaining NP. Inhibiting the inflammatory response can reduce hyperalgesia [33], where the injection of exogenous inflammatory mediators can induce pain [34], supporting the idea that inflammatory mediators play a role in mediating NP. These mediators encompass cytokines, interferons, tumor necrosis factors, chemokines, and colony-stimulating factors. Their production is from immune cells [35] and from glial cells [18, 36, 37, 38], providing a structural basis for the mechanism by which inflammatory mediators mediate NP. Thus, VZV reactivation in PHN serves as the etiological factor for nerve damage, with cytokines playing a crucial role in mediating NP.

3. Cytokines

3.1 Overview of Cytokines Associated with PHN

Cytokines are proteins with low molecular weight that possess diverse biological functions. These proteins are predominantly secreted by immune cells. Additionally, other cell types, including keratinocytes, dendritic cells in the skin, and neuroglia within the central nervous system (CNS), also contribute to cytokine secretion [39, 40, 41]. The release of these cytokines is typically triggered by injury and inflammation [42]. Cytokines exert their biological functions by binding to specific receptors, and regulating cell growth, differentiation, and tissue repair. They are particularly important in stress reactions such as injury, pain, and infection. The properties of cytokines are related to the microenvironment and most have dual effects in different situations [43]. IL-1\beta promotes neuronal sensitization [44, 45]. Pro-inflammatory cytokines include IL-1, IL-6, IL-18 and TNF-\alpha. ILs mainly participate in the proliferation, differentiation, and activation of immune cells, whereas TNF-\alpha can activate cytotoxic T cells and promote the production of other cytokines, collectively enhancing the inflammatory response. Anti-inflammatory cytokines, such as IL-4, IL-10, soluble IL-2 receptor (sIL-2R) antagonists, and TNF-binding proteins, primarily inhibit inflammation to prevent excessive inflammatory responses that could damage the body. However, IL-10 additionally facilitates the activation and expansion of B cells [46], thereby sustaining autoimmune responses (Fig. 1 shows the inflammatory response of immune cells). Under pathological conditions, an imbalance in cytokine levels can contribute to disease progression. For instance, following nerve injury, cytokines secreted by immune cells exert direct effects on neural signaling by binding to homologous receptors on neurons, microglia, and astrocytes within the spinal cord, DRG, and brain. Neuronal activation is not solely dependent on receptor-mediated interactions and cellular contacts but is also regulated through a broader network influenced by cytokine activity [47]. Consequently, these cytokines establish a communication network between immune cells and neurons, involved in the modulation of neural responses [48].

Recent research indicates that PHN is often accompanied by an inflammatory response [10], evidenced by the presence of various cytokines at the injury site, adjacent areas, and even in the plasma [49, 50]. These include TNF-\alpha, ILs, interferon gamma (IFN-\gamma), various chemokines, and oxidative stress-related factors. Collectively, these factors are pivotal in the onset and advancement of NP. Among them, TNF-\alpha, IL-1\beta, IL-6, IL-18, and IL-10 have been more extensively studied in relation to PHN. Other cytokines, such as IFN-\gamma, IL-2, IL-17 and IL-23, have been less well studied in relation to PHN. In untreated animal models [34, 51, 52, 53, 54], intrathecal injections of cytokines such as IL-1\beta, IL-18, TNF, and IL-6 have been observed to directly induce pro-nociceptive effects, leading to hyperalgesia. Cytokines are both important members of the immune system and mediators of pain-related signals. Specifically, TNF-\alpha, IL-1\beta, and IL-6 have been implicated in the development of NP across animal models, including PHN. These cytokines, produced by both neuroglia and immune cells, share common functions such as mediating pain-related cation channel expression, amplifying inflammatory responses, and activating glial cells. In the context of nerve injury, inflammatory cytokines act on nociceptor terminals to initiate pain pathways [55]. Additionally, neuronal activation triggers reciprocal cytokine release, further promoting inflammation. Prolonged inflammation leads to altered sensory nerve fiber signaling, which persists even after inflammation and injury have healed. In summary, it can be hypothesized that cytokines are closely related to the development PHN. This paper explores the signaling pathways of TNF-\alpha, IL-1, IL-6, IL-18, and IL-10, elucidating their roles in the pathogenesis of PHN.

3.2 Signaling of Cytokines

3.2.1 Overview of TNF-\alpha Signaling

TNF-\alpha is intricately involved in the pathogenesis of NP. This cytokine is primarily synthesized by macrophages and acts as a versatile systemic inflammatory mediator. Structurally, TNF-\alpha comprises a signal peptide and two domains, existing in monomeric, dimeric, or trimeric forms, with dimers exhibiting the highest biological activity. Two different receptors, TNF receptor 1 (TNFR1) and TNFR2, are responsible for mediating TNF-\alpha signaling [56]. TNFR1 is broadly expressed and can induce apoptosis, while TNFR2 is predominantly found on specific cell types like immune and endothelial cells, involved mainly in anti-apoptotic signaling. TNF-\alpha influences a variety of biological processes through its interaction with receptors TNFR1 and TNFR2. Through its interaction with TNFR1, TNF-\alpha triggers the activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-\kappaB) pathways, initiating downstream signaling processes [57, 58, 59]. On the other hand, when TNF-\alpha binds to TNFR2, it recruits TNF receptor-associated factor 2 (TRAF2) along with cellular inhibitors of apoptosis proteins 1 and 2 (cIAP1/2), thus activating the non-canonical NF-\kappaB pathway (Table 1, Ref. [60, 61, 62, 63, 64, 65, 66]).

3.2.2 Overview of IL-1\beta Signaling

IL-1\beta, another cytokine, contributes to the initiation and advancement of NP. IL-1\beta is an inactive precursor peptide that undergoes cleavage and activation by IL-1\beta-converting enzyme caspase-1 during inflammation, leading to its extracellular secretion [67]. IL-1\beta initiates signal transduction primarily through the IL-1\beta R-associated kinase (IRAK) pathway. Upon binding, IL-1\beta forms a heterotrimeric complex with IL-1R type I (IL-1R1) and IL-1R accessory protein (IL-1RAcP). This interaction triggers the activation of IRAK4, resulting in IRAK4 autophosphorylation and phosphorylation of IRAK1 and IRAK2. Subsequently, TRAF6 is recruited and activated, which then activates members of the MAPK kinase kinase family. This cascade leads to NF-\kappaB-inducing kinase phosphorylation, facilitating nuclear translocation of NF-\kappaB and subsequent regulation of gene expression [68]. IL-1\beta signaling, similar to TNF-\alpha, activates both the NF-\kappaB and p38-MAPK pathways, promoting the increased expression of genes such as IL-6, monocyte chemotactic protein-1, cyclooxygenase-2, IL-1\alpha, and IL-1\beta [61].

3.2.3 Overview of IL-6 Signaling

IL-6 is a small molecular weight protein secreted by various immune cells. It transmits signals via the ligand-binding IL-6R alpha (IL-6R\alpha) and the signaling component gp130 (CD130) [69]. IL-6 signaling is primarily mediated through three main pathways: first, IL-6 binds to its receptor (IL-6R) to form a complex. This complex subsequently interacts with gp130, which activates intracellular signal transduction, ultimately leading to downstream signaling cascades and gene expression. sIL-6R binds to IL-6 and forms a complex with gp130, initiating signal transduction. Additionally, the interaction between IL-6 and the IL-6R\alpha-gp130 complex initiates signal transduction via Janus kinases (JAKs) and signal transducers and activators of transcription (STATs), which results in STAT3 phosphorylation, subsequent transcriptional activation in T cells, and the triggering of diverse biological effects [62].

3.2.4 Overview of IL-18 Signaling

IL-18 is a protein that mediates its action through a receptor belonging to the IL-1R family. The IL-18R on neurons and glial cells activates important signaling pathways. IL-18 binds to IL-18R\alpha, which then binds to IL-18R\beta to form a trimer [70, 71, 72, 73, 74]. The intracellular domain of IL-18R includes a Toll/IL-1R homology (TIR) domain, which is the same as that in Toll-like receptors. This TIR domain enables MyD88 to attach and relay signals into the cell. IL-18 activates the transcription factor NF-\kappaB [63] and activator protein-1 (AP-1) through signaling molecules such as MyD88, IRAK, and TRAF6 (Table 1).

3.2.5 Overview of IL-10 Signaling

IL-10 exhibits analgesic effects and is secreted and recognized by a range of immune cells. Its main function in vivo is to suppress inflammation by downregulating the production of various pro-inflammatory factors. The functional IL-10R complex comprises a tetramer with two ligand-binding subunits and two auxiliary signaling subunits [75]. The canonical IL-10 signaling pathway involves the JAK/STAT pathway (Table 1) [64]. IL-10 binding to the extracellular domain of IL-10R1 triggers the phosphorylation of JAK1 and tyrosine kinase 2 (TYK2), which in turn activates the transcription factor STAT3. Furthermore, IL-10 reduces NF-\kappaB activation by diminishing its DNA binding ability and inhibiting the activity of I\kappaB kinase. Simultaneously, IL-10 activates AP-1 and NF-\kappaB, promoting the differentiation of CD8+ T cells. In monocytes, IL-10 activates p85 triiodophosphate and p70 S6-kinases. However, blocking these pathways affects the proliferation-regulating activity of IL-10 but not its anti-inflammatory effects.

While these cytokines exhibit specificity in their biological functions depending on the microenvironment, they share common downstream signaling pathways. Notably, the MAPK and NF-\kappaB signaling pathways play a significant role in pain sensitization, the expression of cation channels, and the processes of neuroinflammation. The activation of JAK enhances the sensitivity of the transient receptor potential vanilloid 1 (TRPV1), leading to peripheral sensitization. TNF-\alpha is critical for Na⁺ channel expression via the p38-MAPK pathway, which simultaneously stimulates the production of TNF-\alpha by microglia. IL-1\beta influences pain transmission by modulating ion channels, including TRPV1 and the voltage-gated sodium channel alpha subunit 9 (Nav1.7), through activation of the NF-\kappaB and p38-MAPK systems. IL-6 induces JAK and protein kinase C (PKC) activation, contributing to chronic pain. IL-18 promotes inflammation and increases pain sensitivity through NF-\kappaB transcription. IL-10 may exert its effects by modulating these signaling pathways (Fig. 2).

4. The Role of Cytokines in PHN

Immune cells and glial cells produce a range of cytokines that contribute to both peripheral and central sensitization. Cytokines sustain pain signaling by influencing injury receptors and/or central spinal cord neurons. Cytokines upregulate the expression of pain-related cation channels, including Nav1.3, Nav1.7, Nav1.8, and Ca²⁺, and to activate neuroglial cells. Increased levels of TNF-\alpha , IL-6, and IL-1\beta, as well as other inflammatory mediators, have been observed at the site of nerve injury and in adjacent areas. Low concentrations of cytokines promote neuronal survival and growth and favor post-injury nerve repair, whereas high concentrations of cytokines induce neuronal apoptosis. The peripheral ends of injury receptors form tree-like structures in tissues and organs [76]. These sites are in close proximity to keratinocytes and immune cells and contribute to immunomodulation of injury receptor function. In the context of high-frequency afferent input resulting from tissue damage, a cascade of cytokines targets the ends of sensory nerve fibers known as injury receptors. This interaction initiates the activation of pain pathways, leading to neuronal activation and subsequent reciprocal stimulation of various cytokine-producing cells [55]. Notably, prolonged inflammation alters injury sensory processing, which persists even after inflammation and wound healing, creating a “neuropathic” like phenotype. In the CNS, the types of glial cells include astrocytes, oligodendrocytes, and microglia. Among them, astrocytes and microglia have been the focus of extensive research in the context of NP. It has been proposed that the p38-MAPK system can be activated by spinal astrocytes to promote pain sensitization [77]. Moreover, astrocytes regulate neuroplasticity [78]. Following inflammation, activated microglia undergo transformation into macrophage-like cells [79] that release cytokines such as TNF-\alpha, IL-1\beta, IL-6, and IL-18, affecting synaptic signaling and pain transmission via the p38-MAPK system [80, 81, 82]. Cytokines released from glial cells at the spinal cord level can induce pain secondary to neuronal sensitization (Fig. 3).

4.1 TNF-\alpha

In a meta-analysis study [83], TNF-\alpha levels were evaluated in the body fluids of 113 participants, revealing higher TNF-\alpha levels in patients with PHN compared to those who did not develop PHN after HZ. In a mouse model of PHN induced by HSV-1, elevated TNF-\alpha levels were linked to PHN [12, 25]. These findings indicate that increased TNF-\alpha levels are linked to the occurrence of PHN. Strangfeld et al. [84] observed an increased risk of HZ with the use of TNF-\alpha inhibitors [85]. Interestingly, among patients who developed HZ while using TNF-\alpha inhibitors, there was a lower subsequent incidence of PHN, suggesting a potential role for TNF-\alpha in PHN development. An experimental study has demonstrated that intrathecal injection of exogenous TNF-\alpha can promote pain-induced hyperalgesia and mechanical allodynia [34]. Conversely, TNF-\alpha inhibitors administered via the same route can alleviate chronic pain [86]. This further confirms the crucial role of TNF-\alpha in the pathogenesis of PHN. Consequently, TNF-\alpha inhibitors emerge as promising candidates for the management of chronic pain associated with PHN.

At low concentrations, TNF-\alpha promotes neuronal survival and growth, whereas at high concentrations, TNF-\alpha induces neuronal apoptosis. In the CCI model of rat sciatic nerve-induced NP, TNF-\alpha expression is detected at the injury site [87]. Similar results have been observed in biopsies of human NP lesions [88]. Exogenous TNF-\alpha injected into the DRG of CCI roots causes ectopic pain, suggesting that the cause of NP is not the nerve injury itself, but rather the action of inflammatory mediators following nerve injury [28, 32]. In NP models following nerve injury, TNF-\alpha plays a pivotal role in activating other cytokines [89]. TNF-\alpha binds to its receptors and promotes the activation of inflammatory cells via NF-\kappaB, triggering an inflammatory cascade [90]. TNF-\alpha binds to its receptor and activates the NF-\kappaB signaling pathway to mediate aberrant expression of voltage-gated Na⁺ channels (VGSCs) or Na⁺ currents [91, 92]. A study has shown that exogenous TNF-\alpha administered around nerve leads to persistent mechanical allodynia [90]. Zang et al. [92] demonstrated that TNF-\alpha induces the upregulation of Nav1.3 expression in the DRG by activating NF-\kappaB, and intrathecal injection of an NF-\kappaB inhibitor significantly alleviates mechanical allodynia induced by the perisciatic injection of recombinant rat TNF-\alpha. This indicates that TNF-\alpha mediates the expression of VGSCs in the DRG via the NF-\kappaB system, contributing to the development of NP [93, 94, 95]. Furthermore, TNF-\alpha enhances membrane cation conductance in a non-voltage-gated manner, resulting in overall neuronal hyperexcitability, further exacerbates NP [95].

TNF-\alpha is involved as a pro-inflammatory cytokine in the interaction between neuroimmune cells and glial cells in sensory ganglia and is essential for the promotion of PHN [96, 97]. Following ischemic, inflammatory, or traumatic nerve tissue damage, TNF-\alpha rapidly increases in regions such as the spinal dorsal horn, locus coeruleus, and hippocampus [98, 99, 100, 101]. TNF-\alpha mediates the central mechanisms of NP through neuroglial cells. Immunofluorescence staining has demonstrated the presence of TNF-\alpha on the surface of astrocytes. TNF-\alpha, through G protein-coupled receptor C-X-C chemokine receptor type 4, triggers the production of IL-1, IL-6, and ATP. These substances increase neuronal activity, and contribute to NP [80, 102]. The TNF/TNFR1 signaling pathway contributes to NP by downregulating inward rectifying K⁺ channels (Kir4.1) in astrocytes, disrupting K⁺ homeostasis. Microglial cells have been shown to participate in the pathogenesis of NP [103, 104]. Following nerve injury and inflammation [80, 105, 106, 107, 108], activated microglia secrete pro-inflammatory cytokines mediated by the p38-MAPK system including TNF-\alpha, IL-1, IL-6, C-C motif chemokine ligand 2, and C-X3-C motif chemokine ligand 1, affecting synaptic signal transmission and pain transmission. TNF-\alpha promotes Na⁺ ion influx and lowers excitability thresholds through activation of the p38-MAPK pathway, thereby contributing to NP [91]. For instance, spinal nerve injury in rats induces allodynia, accompanied by elevated levels of TNF-\alpha and phosphorylated p38. Inhibitors of TNF-\alpha or p38 can alleviate this allodynia. TNF-\alpha binds to its receptor and activates the NF-\kappaB signaling pathway, whereas activation of the N-methy1-D-aspartate (NMDA) receptor is associated with the expression of NF-\kappaB [109]. NMDA receptors are involved in peripheral, spinal cord, and cerebral pain pathways by potentiating excitatory postsynaptic currents [110]. Thus, NMDA may be a potential therapeutic target for PHN.

TNF-\alpha is an important mediator in the pathogenesis of NP in the CNS and the peripheral nervous system. It acts in concert with various mediators, including ILs, nerve growth factors, chemokines, and IFNs, coordinating pain signal transmission through the NMDA, ATP, and MAPK signaling pathways.

4.2 IL-1\beta

IL-1\beta, belonging to the IL-1 family, is primarily produced by activated macrophages and exhibits different biological effects. Zhao et al. [111] reported increased levels of IL-1 in the cerebrospinal fluid of patients with PHN. In a meta-analysis involving 1373 participants, researchers confirmed that in patients with HZ, the expression of IL-6 and IL-1\beta was higher in those who developed PHN than in those with HZ without PHN [83]. However, Cao et al. [112] used a protein array to examine 40 common inflammatory factors in the skin lesion tissues of patients with PHN and found that only IL-1\alpha was significantly elevated, albeit with low specificity, whereas there was no difference in expression of the other 39 inflammatory factors, including IL-1\beta. The contradictory results might stem from differences in detection sites. The epidermis in skin affected by PHN exhibits increased thickness compared to normal skin, suggesting possible structural or molecular changes. Immunohistochemical data have consistently shown reduced nerve ending density in the epidermis of PHN skin [113, 114, 115, 116, 117]. While various cell types can express IL-1, barrier cells such as epithelial cells normally express high amounts of IL-1. The decreased IL-1 expression in PHN may be linked to cellular changes such as the loss of specific cell types in the affected skin. Moreover, the molecular pathological alterations observed in the skin affected by PHN could lead to decreased IL-1 expression. This indicates that the persistent and chronic pain experienced by PHN patients may not be directly linked to skin inflammation.

Under normal conditions, IL-1\beta expression is low. After peripheral nerve injury, IL-1\beta expression is elevated in glial cells, and certain immune cells within the spinal cord, leading to diverse effects on the nervous system. Similar to TNF-\alpha, IL-1\beta signaling participates in pain through activation of the NF-\kappaB and p38-MAPK pathways. In the peripheral DRG, IL-1\beta acts on TRPV1 and IL-1R to modulate pain sensitivity [118]. TRPV1, part of the TRP family, is closely associated with the perception of harmful stimuli and pain generation. Activation of TRPV1 can regulate Ca²⁺ influx through voltage-dependent Ca²⁺ channels (VDCCs) [119]. This process results in the release of neuropeptides and excitatory amino acids from nerve terminals, which ultimately leads to the perception of pain in the cortex [120]. JAK and PKC inhibitors alleviate sensitization of TRPV1. TRP inhibitors help prevent the release of injurious substances, paving the way for the discovery of novel analgesics. Upon binding to IL-1Rs, IL-1\beta also promotes prostaglandin synthesis, indirectly sensitizing pain receptors to induce pain. Biologically active IL-1\beta is formed from the precursor IL-1\beta by cleavage through certain enzymes, with matrix metalloproteinases (MMPs) playing a significant role in this process. Among these, MMPs affect the release of IL-1\beta. Increased activity of MMP9 and MMP2 due to nerve injury promotes cleavage of the IL-1\beta precursor, resulting in the formation of biologically active IL-1\beta. Inhibitors of MMP9 or MMP2 can reduce the biological activity of IL-1\beta, significantly alleviating NP behaviors in animals. In addition, at central sites, IL-1\beta induces nociceptive sensitization [109] by promoting the release of substance P from \alpha-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid or NMDA receptors [121], an ionotropic glutamate receptor mediating excitatory neurotransmitter transmission that plays a crucial role in the pain pathway. Activation of the NMDA receptor leads to Ca²⁺ inward flow, promoting central sensitization [122]. In conclusion, IL-1\beta promotes PHN by directly or indirectly increasing neuronal excitability. Modulation of IL-1\beta, TRPV1 [123], and NMDA receptors may serve as new analgesic options to alleviate NP in patients with PHN.

Therefore, therapeutic blockade of these proteases holds promise for limiting the release of biologically active IL-1\beta and potentially alleviating neuropathic inflammation to achieve relief from NP.

4.3 IL-6

IL-6 is considered an early marker of injury, playing a regulatory role in both the immune and nervous systems. It suppresses immune function by inducing macrophages to release transforming growth factor beta (TGF-\beta), which modulates the acute phase inflammatory response [69]. Arruda et al. [124] observed elevated IL-6 mRNA levels in the spinal dorsal and ventral horns of rats following peripheral nerve injury. Similarly, studies involving human brain vascular adventitial fibroblasts (HBVAFs) and human peripheral nerve cells infected with VZV revealed significant increases in IL-6 transcription and expression levels, which lead to the loss of integrity of vascular and neural barrier and continued viral replication [125, 126, 127].

Research has shown that patients with HZ who later develop PHN have significantly higher IL-6 levels than those who do not develop PHN [128]. This suggests that elevated IL-6 expression is associated with inflammatory responses leading to nerve damage and promoting the onset and progression of NP. Downregulation of IL-6 expression can significantly alleviate pain. Saxena et al. [129] observed that during the treatment of neuralgia in patients with HZ, IL-6 mRNA expression was significantly decreased following substantial pain relief. Lin et al. [130] analyzed IL-6 levels in patients with PHN based on pain severity and found significant differences among different severity groups, with particularly elevated IL-6 levels in patients with severe pain. Furthermore, IL-6 levels are correlated with short-term prognosis in patients with PHN. However, a study by Zak-Prelich et al. [131] reported conflicting results, possibly due to a smaller sample size and a broader age range.

IL-6 is associated with peripheral mechanisms of pain onset. Under physiological conditions, low levels of IL-6 are beneficial for normal development and repair of the nervous system; however, excessive production of IL-6 can lead to neurological damage. A study has shown that direct injection of IL-6 into rodent joints results in sustained sensitization of injury-sensing C fibers [120]. IL-6-mediated inflammatory responses may be linked to pain hypersensitivity. Following peripheral nerve injury, IL-6 and IL-6R are highly expressed in neurons. Similar to IL-1\beta and TNF-\alpha, IL-6 enhances Na⁺ [132] and Ca²⁺ [133] currents in peripheral nerve terminals, triggering action potential firing. This increases membrane excitability and reducs the pain threshold, leading to peripheral sensitization. IL-6 also induces activation of JAK and PKC, increasing TRPV1 sensitivity and inducing pain [134, 135].

IL-6 is a neurogenic signaling mediator that transmits injury signals to the CNS [117]. Microglia activation promotes the PHN. After nerve injury, IL-6 mediates NP through the JAK2/STAT3 and ciliary neurotrophic factor (CNTF)/STAT3 signaling pathway [136, 137]. Activation of the JAK2/STAT3 pathway promotes microglia and astrocyte activation, leading to cytokine release and amplifying neuroinflammation. The initiation and progression of inflammatory cascades from the peripheral regions to CNS are mediated by the CNTF-STAT3-IL-6 signaling axis. Blocking the CNTF-STAT3-IL-6 pathway can alleviate nerve inflammation in the DRG and spinal cord, thereby reducing pain following injury [137]. Administering anti-IL-6 antibodies significantly reduces JAK2/STAT3 signaling and pain behavior in rats. Overall, these studies suggest that targeting IL-6 could be advantageous in alleviating inflammatory responses and modulating the impact on nociceptors.

4.4 IL-18

IL-18 is also a cytokine involved in the regulation of the immune response [71]. It has been shown to be associated with chronic pain, such as NP, osteoarthritis pain, and cancer pain [72, 73, 74]. Khazan et al. [138] confirmed that IL-18 levels are linked to the risk of PHN. At the peripheral site, IL-18 ,which produced by immune cells, stimulates the transcription of Toll-like receptors and NF-\kappaB, promoting the release of inflammatory mediators and mediated pain signaling [139, 140]. IL-18 modulates pain by influencing ion channels and receptors mediating pain in the nervous system [72, 141]. Increased IL-18 expression has been observed in various models of NP resulting from nerve injury. IL-18 plays a pivotal role in NP regulation through injurious sensory transmission [141, 142, 143, 144]. In addition, IL-18 is crucial in regulating the activity of glial cells [145, 146, 147]. Blocking the IL-18 signaling pathway inhibits glial cell hyperactivity and subsequent activation of Ca²⁺ dependent signaling pathways [148]. IL-18-mediated interactions between microglia and astrocytes are pivotal for NP [72]. Studies [53, 144] have shown that microglia contribute to inflammation and NP by producing IL-18. Additionally, oligodendrocytes have been implicated in neuroinflammation via IL-18 production [149]. Immune-mediated inflammation significantly influences NP development, with IL-18 mediating microglial and astrocytic interactions that release proinflammatory cytokines, chemokines, and other signaling molecules [72], thereby amplifying pain signals and recruiting immune cells to injury sites [150]. Moreover, IL-18 triggers cytokine production through inflammatory vesicle complexes, further enhancing the immune response [151]. These findings collectively emphasize the critical role of IL-18 in the pathogenesis of PHN.

4.5 IL-10

Uçeyler et al. [152] showed that IL-10 gene expression increases immediately after nerve injury, with a secondary peak observed within 45 days. Khan et al. [153] found that minimal inflammation of peripheral nerves following injury had no significant effect on IL-10 levels in sciatic nerve of rats across four types of sciatic nerve injuries. Partial nerve injury decreased IL-10 levels in the affected nerves, whereas complete nerve transection increased IL-10 expression. This implies that IL-10’s involvement in NP etiology may vary depending on the specific nature of the nerve injury. After nerve injury, IL-10 activates microglia in the CNS to mediate NP [154]. IL-10 stimulates G protein-coupled receptor 40, along with intracellular signaling pathways such as STAT3, leading to increased \beta-endorphin expression and secretion [155]. Sharma et al. [156] identified the expression of IL-10 receptors in cortical neurons, where they mediate neuroprotection through the activation of the PI3K/AKT and STAT3 pathways. Additionally, Huang et al. [157] demonstrated that IL-10 attenuates NP by downregulating Nav1.7 in the DRG of rats. Following sciatic nerve crush injury in mice [158] , IL-10 secretion by macrophages is increased, which subsequently lowers the levels of chemokines and cytokines. Additionally, IL-10 deficiency impairs axonal regeneration and hinders the recovery of nerve functions. Atkins et al. [159] studied the effects of IL-10 on nerve regeneration in anesthetized C57 Black-6 mice following left sciatic nerve sectioning and resealing with four extraneous nerve sutures. The authors injected IL-10 (125 or 500 ng) at the repair site before and after nerve sectioning. Their findings revealed that a low dose of IL-10 at the sciatic nerve repair site facilitated better axonal regeneration, whereas a high dose did not. This suggests that optimal levels of IL-10 promote nerve regeneration, while prolonged high levels are detrimental to nerve repair. A study has shown that the induction of VZV-specific T lymphocytes is accompanied by increased IL-10 expression [152].

Jenkins et al. [160] showed that elevated levels of IL-10 are involved in the immune response to certain viruses. The intensity of the inflammatory response triggered by VZV directly influences the production of IL-10, which increases proportionally to mitigate the inflammation. However, high IL-10 levels can inhibit T helper1-specific cell-mediated immunity, allowing the virus to spread more effectively. While IL-10 enhances anti-inflammatory effects, it can also prolong inflammation, explaining why chronically high IL-10 levels impede nerve damage repair. In a study seeking predictors of neuralgia duration in HZ patients [161], a marked elevation in IL-10 levels was observed in the serum of patients experiencing severe HZ. IL-10 were positively correlated with neuralgia duration and pain severity, leading to the conclusion that IL-10 levels are an independent risk factor for PHN. Although most studies suggest that IL-10 has a positive effect on relieving NP, NP in these studies was short-lived and mostly inflammatory. PHN is a chronic NP lasting more than 3 months, caused by nerve injury. Persistent elevation of IL-10 not only prolongs the inflammatory response but also impedes nerve repair. From this perspective, IL-10 may mediate the development of PHN. Future studies on the mechanism of IL-10 involvement in PHN are needed (Table 2, Ref. [72, 80, 90, 91, 92, 95, 102, 110, 119, 120, 132, 133, 141, 152, 162]).

5. Future Research Perspectives

Cytokines are essential for sustaining NP. PHN, as a typical NP, is closely associated with inflammatory cytokines. Cytokines are generally secreted by multiple cells and can act on various target cells. Moreover, a single cytokine can trigger its target cells to produce additional cytokines, initiating a cascade of effects. In fact, neuroinflammation, driven by the interplay between pro-inflammatory and anti-inflammatory cytokines, serves as a fundamental mechanism underlying the onset of PHN. The above-mentioned role of cytokines in PHN is unquestionable, but there are few studies on the effects of cytokine antibodies on PHN. Cell and organ culture models, as well as animal studies, have demonstrated promising outcomes with anti-cytokine medications and pathway inhibitors for alleviating NP. However, clinical evidence remains sparse regarding the role of anti-cytokine drugs in NP. Moreover, clinical trials [163, 164, 165, 166] targeting TNF-\alpha antagonists in sciatic neuropathy treatment have notably failed to eliminate NP. Given the complex interplay in neuroinflammatory balance, targeting specific cytokines poses a challenge. An alternative therapeutic approach may involve regulating the cytokine cascade more comprehensively through growth factors. In a clinical trial using ibudilast to treat diabetic NP, patients experienced effective pain relief [167] due to the fact that ibudilast inhibits the activation of glial cells and reduces the release of cytokines. Valerian theophylline reduces pain by inhibiting microglia activity [168]. Thus, future research targeting entire systems [169, 170, 171, 172, 173, 174] such as inflammatory cytokines, chemokines, MAPK, and neuroglial cells is expected to emerge as promising avenues for comprehensive PHN treatment. Due to the strict human specificity of VZV, how to use VZV strains in rodent models to overcome this specific infection remains to be determined by researchers, which will also provide reliable models for PHN treatment research.

6. Conclusion

The mechanisms underlying the development of PHN are complex and involve many factors, with cytokines playing a critical role. Cytokine-induced neuroinflammation is the root factor promoting PHN. As important molecules in neuroimmunity, cytokines regulate pain signaling pathways in both the peripheral nervous systems and CNS, activate glial cells, and increase neuronal excitability, thus promoting the development of PHN. Given that cytokines are crucial for nerve repair, rather than completely blocking cytokine production, targeting cytokine-dependent responses, such as neuronal excitability and neuroinflammation, could be a better treatment option for PHN. Moreover, since cytokines regulate pain in PHN patients through a complex network, future treatment strategies should target specific actions across multiple systems simultaneously. Therefore, further understanding of the effects of cytokines on changes in neuronal excitability, neuroinflammation and pain could help identify novel therapeutic targets, making it possible to effectively treat chronic pain in PHN patients without impairing nerve repair.

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Funding

co-construction science and technology programme project of the Zhejiang Provincial Administration of Traditional Chinese Medicine(GZY-ZJ-KJ-23088)