IL-23/IL-17A/TRPV1 axis produces mechanical pain via macrophage-sensory neuron crosstalk in female mice

Luo, Xin; Chen, Ouyang; Wang, Zilong; Bang, Sangsu; Ji, Jasmine; Lee, Sang Hoon; Huh, Yul; Furutani, Kenta; He, Qianru; Tao, Xueshu; Ko, Mei‐Chuan; Bortsov, Andrey V.; Donnelly, Christopher R.; Chen, Yong; Nackley, Andrea G.; Berta, Temugin; Ji, Ru-Rong

doi:10.1016/j.neuron.2021.06.015

Cited by 112 publications

(101 citation statements)

References 73 publications

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“…We recently showed that IL-17A was required for IL-23induced mechanical pain (Luo et al, 2021). At the baseline, THP-1 cells secreted low levels of IL-17A (3-7 ng/ml), but this secretion was significantly increased by co-application of PTX (1 mg/ml, 24 h) and estrogen (1 ng/ml, 24 h), (p < 0.05, vs control, Figure 7B).…”

Section: Macrophages Release Il-23 and Il-17amentioning

confidence: 83%

“…Intense and persistent activation of C-fibers, such as TRPV1 and TRPA1 agonists, is known to produce remarkable edema and neurogenic inflammation (33,34). Our recent study shows necessity of TRPV1 for IL-23-induced mechanical pain in females (27). To this end, we measured paw thickness 3 hours after intraplantar injection of IL-23 (100 ng) or vehicle (PBS) in male and female mice.…”

Section: Il-23 Induces Mechanical Allodynia In Female Mice But Not Malesmentioning

confidence: 98%

“…Our recent study showed comparable expression of Trpv1 mRNA in male and female mice (Luo et al, 2021). Given the important role of TRPV1 in immune cells and nociceptor interactions, we conducted additional analysis of Trpv1 expression using a cohort of 10 male and female mice (n = 5 for each sex).…”

Section: Female and Male Mice Exhibit Distinct Size Distributions Of Trpv1-positive Neuronsmentioning

confidence: 99%

“…Our recent study showed that IL-23 does not activate nociceptors directly. Instead, IL-23 produces IL-17A in macrophages to activate nociceptors (Luo et al, 2021). To further address the question of IL-23 release and IL-23 signaling in macrophages, we conducted ELISA analysis in THP-1 cells, using a well-characterized cell line of human macrophages.…”

Section: Macrophages Release Il-23 and Il-17amentioning

confidence: 99%

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IL-23 Enhances C-Fiber-Mediated and Blue Light-Induced Spontaneous Pain in Female Mice

Luo

et al. 2021

Front. Immunol.

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The incidence of chronic pain is especially high in women, but the underlying mechanisms remain poorly understood. Interleukin-23 (IL-23) is a pro-inflammatory cytokine and contributes to inflammatory diseases (e.g., arthritis and psoriasis) through dendritic/T cell signaling. Here we examined the IL-23 involvement in sexual dimorphism of pain, using an optogenetic approach in transgenic mice expressing channelrhodopsin-2 (ChR2) in TRPV1-positive nociceptive neurons. In situ hybridization revealed that compared to males, females had a significantly larger portion of small-sized (100-200 μm2) Trpv1+ neurons in dorsal root ganglion (DRG). Blue light stimulation of a hindpaw of transgenic mice induced intensity-dependent spontaneous pain. At the highest intensity, females showed more intense spontaneous pain than males. Intraplantar injection of IL-23 (100 ng) induced mechanical allodynia in females only but had no effects on paw edema. Furthermore, intraplantar IL-23 only potentiated blue light-induced pain in females, and intrathecal injection of IL-23 also potentiated low-dose capsaicin (500 ng) induced spontaneous pain in females but not males. IL-23 expresses in DRG macrophages of both sexes. Intrathecal injection of IL-23 induced significantly greater p38 phosphorylation (p-p38), a marker of nociceptor activation, in DRGs of female mice than male mice. In THP-1 human macrophages estrogen and chemotherapy co-application increased IL-23 secretion, and furthermore, estrogen and IL-23 co-application, but not estrogen and IL-23 alone, significantly increased IL-17A release. These findings suggest a novel role of IL-23 in macrophage signaling and female-dominant pain, including C-fiber-mediated spontaneous pain. Our study has also provided new insight into cytokine-mediated macrophage-nociceptor interactions, in a sex-dependent manner.

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Section: Macrophages Release Il-23 and Il-17amentioning

confidence: 83%

Section: Il-23 Induces Mechanical Allodynia In Female Mice But Not Malesmentioning

confidence: 98%

Section: Female and Male Mice Exhibit Distinct Size Distributions Of Trpv1-positive Neuronsmentioning

confidence: 99%

Section: Macrophages Release Il-23 and Il-17amentioning

confidence: 99%

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IL-23 Enhances C-Fiber-Mediated and Blue Light-Induced Spontaneous Pain in Female Mice

Luo

et al. 2021

Front. Immunol.

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“…Taking all these observations together, mechanosensory stimuli impinging on skin may stimulate dermal macrophages, and the macrophages then make the NGF concentration optimal for neurons to respond to stimuli via an SNX25-Nrf2 signaling pathway. A recent report showed that IL-23/IL-17A/TRPV1 axis regulates female-speci c mechanical pain via macrophage-neuron interactions 48 . The present study has several overlaps (mechanisms originated from macrophages and involvement of TRPV1) with the report, but the SNX25-Nrf2 axis is not female-speci c (most of the present data were obtained from male mice), suggesting that both molecular axes may cooperate in mechanical pain sensation.…”

Section: Discussionmentioning

confidence: 99%

Dermal macrophages set pain sensitivity by modulating tissue NGF levels through SNX25–Nrf2 signaling

Tanaka

Okuda

Terada

et al. 2021

Preprint

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Crosstalk between peripheral neurons and immune cells plays important roles in pain sensation. We identified sorting nexin 25 (Snx25) as a pain-modulating gene in a transgenic mouse line with reduced pain behavior. Snx25 conditional-KO (cKO) in monocyte/macrophage-lineage cells but not in the peripheral sensory neurons reduced pain responses in both normal and neuropathic conditions. Cross transplantation experiments of bone marrows between cKO and wild type (WT) mice revealed that cKO macrophages caused dull phenotype in WT mice and WT macrophages in turn increased pain behavior in cKO mice. SNX25 in dermal macrophages enhances NGF (one of the key factors in pain sensation) production by inhibiting ubiquitin-mediated degradation of Nrf2, a transcription factor that activates Ngf mRNA synthesis. We conclude that dermal macrophages set pain sensitivity by producing and secreting NGF into the dermis in addition to their host defense functions.

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Multifunctional DNA Hydrogel Enhances Stemness of Adipose‐Derived Stem Cells to Activate Immune Pathways for Guidance Burn Wound Regeneration

Zhou

Zeng

Liu

et al. 2022

Adv Funct Materials

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A grade 3 burn is a nonstatic fatal injury, which can lead to complete damage to the skin structure, accompanied by a series of symptoms such as persistent inflammation, pain, pruritus, ulcer, and peripheral neuropathy. Although the primary clinical burn treatment is skin grafting, it cannot comprehensively solve burn symptoms. Here, a multifunctional DNA hydrogel integrated system is conveniently obtained through dynamic cross-linking of the DNA unit, polyacrylamide, and l-ascorbate 2-phosphate (l-A2P) formation of dense hydrogen bonds. The DNA hydrogel is doped with borneol for pain and itch relief. The obtained DNA hydrogel provides a hotbed similar to the extracellular matrix structure in vivo for the growth and development of stem cells, which can regulate cell proliferation, maintain cell viability, and achieve perfect release in a suitable environment. Additionally, the pharmacological wound dressing shell features excellent mechanical behavior, tissue adhesion, and antibacterial properties. Beyond that, the multifunctional DNA hydrogel integrated system can promote macrophage transformation, angiogenesis, and neurogenesis. Notably, the system activates the phosphatidylinositol 3′-kinase (PI3K)-Akt signaling pathway, which helps to promote tissue regeneration. Therefore, the DNA hydrogel integrated system opens the cascade mode of effective integrated treatment of burn wounds, further driving the in-depth study of clinical transformation mechanisms in the future.

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IL-23/IL-17A/TRPV1 axis produces mechanical pain via macrophage-sensory neuron crosstalk in female mice

Cited by 112 publications

References 73 publications

IL-23 Enhances C-Fiber-Mediated and Blue Light-Induced Spontaneous Pain in Female Mice

IL-23 Enhances C-Fiber-Mediated and Blue Light-Induced Spontaneous Pain in Female Mice

Dermal macrophages set pain sensitivity by modulating tissue NGF levels through SNX25–Nrf2 signaling

Multifunctional DNA Hydrogel Enhances Stemness of Adipose‐Derived Stem Cells to Activate Immune Pathways for Guidance Burn Wound Regeneration

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