Myeloid Differentiation Primary Response Protein 88: An Important Therapeutic Target for Chronic Pain

H. Liang, Hanlin Liang, Linbin Fu, Zheng Li, Li Z, Liu Z, Zhiheng Liu
Journal of pain research · 2025 · vol. Volume 18 , pp. 1061–1069 · doi:10.2147/jpr.s487685 · PMID:40061432 · PMC11890100 · W4408109129
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This review details how myeloid differentiation primary response protein 88 (MyD88) plays a crucial role in chronic pain development and maintenance across multiple injury and disease models.

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Abstract

Chronic pain is a major cause of suffering. This interferes with daily functioning and is often accompanied by distress. However, current therapeutic strategies for chronic pain are unsatisfactory because of poor understanding of its mechanisms. Therefore, more comprehensive therapeutic targets must be identified to improve the quality of life of these patients. Myeloid differentiation primary response protein 88 (MyD88) is an adaptor protein of the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families. Recently, overexpression of MyD88 in the spinal and dorsal root ganglia was observed in multiple pain models, which also revealed that MyD88 plays an important role in the development and maintenance of chronic pain. In this review, we summarized the roles and mechanisms of MyD88 in the progression of different pain models, including chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathic pain (DNP), spinal nerve ligation (SNL), chronic constriction injury (CCI), spinal cord injury (SCI) and inflammatory pain.
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Intro

Physiological pain plays an important role in the protection against nociceptive stimulation. However, chronic pain compromises quality of life. Major pathological phenomena of chronic pain include allodynia (pain due to a stimulus that does not normally provoke pain), hyperalgesia (increased pain from a stimulus that normally provokes pain) and spontaneous pain (pain felt without apparent external stimulus). 1 Chronic pain has multiple mechanisms that can exacerbate and maintain pain, including central sensitization and peripheral sensitization. 2 , 3 Several studies had illustrated that many pathological processes are characterized by chronic pain, such as chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathic pain (DNP), spinal nerve ligation (SNL), chronic constriction injury (CCI), spinal cord injury (SCI) and inflammatory pain. However, the mechanisms identified by previous researchers in these pain models have not achieved good clinical conversion. Therefore, there is an urgent need to understand the mechanisms underlying the development and maintenance of pain during therapeutic treatment. Damage to the nervous system causes the release of cytokines, chemokines and pro-inflammatory mediators, which activate resident immune and glial cells and attract circulating leukocytes to the site of injury and throughout the neural pain axis (including the dorsal root ganglia, dorsal horn spinal cord and supraspinal brain areas). A lot of immune cells participate in neuroinflammation including neutrophils, macrophages, dendritic cells, mast cells, T cells, antibody-producing B cells and microglia. These cells release inflammatory mediators, such as tumour necrosis factor, diverse interleukins, reactive oxygen and nitrogen species, bradykinin, growth factors, and prostaglandins, which increase neuronal excitability and suppress inhibitory pathways. The result of these changes is sensitization of the somatosensory signaling pathway and development of neuropathic pain symptoms. 4 Myeloid differentiation primary response protein 88 (MyD88) was discovered in 1990 and was upregulated in the murine leukemic myeloblast cell line M1D+ during IL-6-induced cellular differentiation. 5 MyD88 is mainly composed of an N-terminal death domain (DD), an intermediate domain (INT), and a C-terminal toll-interleukin-1 receptor (TIR) domain. Moreover, the INT domain of MyD88 links DD and TIR. 6 As downstream of the toll-like receptor (TLR) and interleukin-1 (IL-1) receptor family members, MyD88 is a typical adaptor in the inflammatory signaling pathway. Activation of IRAK family kinases leads to a variety of functional outputs, including the activation of nuclear factor-kappa B (NFkB), mitogen-activated protein kinases, and activator protein 1, making MyD88 a central node of inflammatory pathways. TLR2 and TLR4 recruit MyD88 indirectly by bridging the adapter MAL (TIR-domain-containing adaptor protein), whereas other TLRs recruit it directly. 7 , 8 MyD88 plays a central role in connecting the IL-1 receptor (IL-1R) or TLR family members with IL-1R-associated kinase (IRAK). Subsequently, it leads to the activation of nuclear factor-kappa B (NF-κB), activator protein-1 (AP-1), and interferon regulatory factors (IRFs) ( Figure 1 ). 9 MyD88 signaling can lead to distinct outputs depending on the context, usually leading to pro-inflammatory cytokine or type I IFN production. Distinct pathways downstream of IRAK family members regulate these outputs, and the outcome of signaling can be influenced by the cell type and location of signal initiation. 6 Recently, increasing evidence has been reported on the role of MyD88 in pain processing. A deeper understanding of the mechanism of MyD88 in different pain models will pave the way for future studies of MyD88 and its role in weakening or regulating pain. Therefore, the role of MyD88 in different pain models is worth investigating. Figure 1 Schematic illustration demonstrates MyD88 signaling pathways of chronic pain. The binding of HMGB1 and IL-1β to their receptors (TLR2/4 and IL-1R, respectively) activates MyD88 in the DRG and SDH, which phosphorylate NF-κB. Phosphorylated NF-κB subsequently enter the nucleus to regulate the expression of proinflammation cytokine. Which regulates the expression of certain cytokines and activates glial cells. All these signaling events consequently result in central and peripheral sensitizations that produce chronic pain. Schematic illustration demonstrates MyD88 signaling pathways of chronic pain. The binding of HMGB1 and IL-1β to their receptors (TLR2/4 and IL-1R, respectively) activates MyD88 in the DRG and SDH, which phosphorylate NF-κB. Phosphorylated NF-κB subsequently enter the nucleus to regulate the expression of proinflammation cytokine. Which regulates the expression of certain cytokines and activates glial cells. All these signaling events consequently result in central and peripheral sensitizations that produce chronic pain.

Myd88

Inflammation pain often results from the high excitability of peripheral nociceptive sensory fibers to inflammatory mediators. 49 Persistent contact with pro-inflammatory mediators sensitizes peripheral pain-sensing neurons, leading to chronic inflammatory pain. Skin, joints, and gut are particularly susceptible to the development of inflammatory pain. 50 The C-terminal tail region of high mobility group box 1 (HMGB1) binding to TLR5 initiates the activation of NF-kB signaling pathway in a MyD88-dependent manner, leading pro-inflammatory cytokine production and pain enhancement in vivo. 51 Endometriosis is an estrogen-dependent disease with endometrial tissue occurring outside the uterine cavity. 52 Its estimated affect 10% of reproductive age women. 53 In a rat model of endometriosis, Su et al 54 revealed that HMGB1-TLR4-MyD88 signaling pathway in the DRG and SDH might be involved in endometriosis-related hyperpathia. Intrathecal application of LPS-RS-Ultra (LRU) and MIP alleviated mechanical pain by blocking TLR4 and MyD88 expression. Daily oral administration of an inhibitor of IL-1R-associated kinase 4 (IRAK4), a downstream signaling molecule of MyD88, significantly inhibits epithelial cell proliferation and cystic lesion growth. Endometriotic lesion volume was almost completely suppressed in MyD88 −/− mice. 52 Intra-articular (ia) injection of lipopolysaccharide (LPS) can induce inflammatory hyperalgesia in joints. The mechanical nociceptive threshold was reduced in a dose- and time-dependent manner. 55 And LPS-induced joint mechanical hyperalgesia was abolished in TLR4 −/− and MyD88 −/− mice, respectively. 55 This result indicated that the TLR4/MyD88 signaling pathway is involved in the mechanism of inflammatory joint pain. Recently, Cai et al 56 illustrated that the overexpression of fat mass and obesity-associated gene (FTO) could reduce cell apoptosis and inhibit inflammation in the synovial fluid. Inhibitory effect of FTO on LPS-induced cell injury through the miR-515-5p/TLR4/MyD88/NF-κB axis. In another rabbit model of knee osteoarthritis (KOA), Xu et al 57 indicated that Zhuifeng Tonggu (ZFTG) capsules reduced chondrocyte inflammation and apoptosis by suppressing the expression of TLR2, TLR4, and MyD88. Moreover, with the modulation of miR-665 and circRNF121, MyD88 expression is altered in an OA model. 58 In addition, in a model of inflammatory pain treated with LPS paw injection, WT mice produced mechanical hyperalgesia while this performance was absent in TLR4 mutant and MyD88 null mice. 59 Bexarotene was found to play anti-inflammatory and analgesic roles in systemic inflammatory response model triggered by LPS intraperitoneal injection by suppression of TLR4/MyD88/TAK1/NF-κB/COX-2 pathway. 60 Qin et al 61 found that the level of MyD88 mRNA and protein were increased in a dose- and time-dependent manner in intervertebral disc (IVD) degeneration model, in which IVD nucleus pulposus cells treated with LPS. These results from various models suggest that the activation of the MyD88-dependent signaling pathway plays an important role in inflammatory pain ( Figure 4 ).

Conclusion

By reviewing current evidence, we discuss the relationship between MyD88 and chronic pain. These studies provide robust evidence that MyD88 plays a vital role in the development of chronic pain such as CIPN, DNP, neuropathic pain, inflammatory pain, and MIP by various mechanisms. Treatment with the MyD88 homodimerization inhibitory peptide MIP attenuated mechanical allodynia and thermal hyperalgesia caused by chronic pain, indicating that inhibitors of MyD88 may be beneficial therapeutic tools for chronic pain. Moreover, the development of upstream of MyD88 signaling pathway (such as TLR4) inhibitors/modulators also show effective therapeutic effects for the treatment of chronic pain. These findings provide a convincing theoretical basis for the development of drugs targeting chronic pain. However, improved MyD88 inhibitors with fewer side effects should be explored in the future.

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