Neuropathic pain (NP) caused by somatosensory nervous system injury or disease is a common condition, with a global incidence of approximately 1.5% to 8% (Alles and Smith, 2018). NP plays a critical maladaptive role in an organism, as in the case of inflammation, which causes the perception of pain to persist beyond the resolution of the injury, thereby avoiding harmful stimuli and promoting the healing of damaged tissue (Sommer et al., 2018). Different peripheral nerve injuries (PNIs) induce NP, which involve abnormal neuronal responses from the dorsal root ganglion (DRG) to the spinal cord, particularly the spinal dorsal horn (SDH), and ultimately to the cerebral cortex. These injuries also cause a significant neuroinflammatory reaction at the affected sites. Accumulating evidence reports that not only neurons but also nonneuronal cells, can be activated along nociceptive pathways (Deng et al., 2019; Donnelly et al., 2020; Chen et al., 2022; Wang et al., 2022). When activated after injury, nonneuronal cells in the DRGs and spinal cords release proinflammatory mediators (e.g., tumor necrosis factor α (TNF-α)), which can directly or indirectly amplify pain signals and facilitate the maintenance of pain (Li et al., 2019; Luo et al., 2019; Gao et al., 2020). On the other hand, nonneuronal cells release multiple anti-inflammatory mediators, such as interleukin-10 (IL-10), which can control inflammation and nociceptive responses (Ahmad et al., 2021).

Interleukin-24 (IL-24) was originally reported by Jiang et al., 1995 (Jiang et al., 1995). It is encoded by the IL-24 gene, which contains 7 exons and 6 introns and is located on chromosome 1q32–33 (Mitamura et al., 2020). IL-24 is broadly expressed in a variety of immune cells (B cells (Maarof et al., 2010), mast cells, NK cells (Mitamura et al., 2020), monocytes (Dabitao et al., 2018), macrophages (Rao et al., 2021) and T cells (Chong et al., 2020)) and epithelial cells (keratinocytes (Olsan et al., 2018) and fibroblasts (Xu et al., 2021a)). IL-24 belongs to the subfamily of cytokines known as IL-10; however, it has the function of Th2 cytokines, which are widely believed to have a proinflammatory role, thus having the opposite function of IL-10. IL-24 receptors (IL-20R), which belong to the cytokine type II receptor family, can be classified into two types of heterodimeric receptor subtypes: interleukin-20 receptor 1 (IL-20R1)/interleukin-20 receptor 2 (IL-20R2) and interleukin-22 receptor 1 (IL-22R1)/IL-20R2 (Zhong et al., 2022). Although IL-24 is capable of binding to the IL-20R2 subunit (with a short cytoplasmic tail, 282 amino acid residues) alone, receptor activation requires the coexpression of IL-20R1 or IL-22R1 (with a long cytoplasmic tail, 524/660 amino acid residues), which not only enhances the binding affinity but is also necessary for proper receptor function. IL-24 exhibits an equivalent binding affinity of 8 nmol/L to both receptor subtypes (Menezes et al., 2018).

Increased IL-24 expression has been implicated in various autoimmune and allergic disorders with proinflammatory features, including but not limited to psoriasis (Xu et al., 2021a), inflammatory bowel disease (Ónody et al., 2021), systemic lupus erythematosus (Tang et al., 2021), rheumatoid arthritis (Kragstrup et al., 2018) and multiple sclerosis (Muls et al., 2017). Moreover, IL-24 shows a good association with the development of various allergic conditions, including allergic rhinitis, allergic asthma, chronic spontaneous urticaria, allergic contact dermatitis and atopic dermatitis (Mitamura et al., 2020). IL-24 is also well defined as one of the genes that accelerate wound repair and defense against bacterial and viral infections (Kolumam et al., 2017). IL-24 is upregulated in mouse wound marginal keratinocytes, which can reduce infection and accelerate inflammation by secreting a variety of chemokines and inducing the expression of VEGFA, further promoting wound healing. Some studies have shown that the abnormal expression of IL-24 is closely related to the occurrence and development of wrist arthritis and diabetes mellitus (Zhao et al., 2018; Mahmoud et al., 2023). IL-24 is highly expressed in rheumatoid arthritis and spondylarthritis (Persaud et al., 2016). It is not difficult to see that IL-24 is a versatile cytokine and likely plays a role in the modulation of tissue inflammation and autoimmunity. Despite an increasing number of studies investigating the pathological function of IL-24 in neuroimmune-mediated diseases, there is hardly any study that have examined the involvement of IL-24 in the pathophysiology of NP. In this study, we revealed that IL-24 contributed to NP after PNI through IL-20R2 in mice.