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The role of interleukin (IL)-23 in regulating pain in arthritis

Abstract

Current understanding of IL-23 biology, with its link to other pro-inflammatory cytokines, for example, IL-17 and granulocyte macrophage-colony stimulating factor (GM-CSF), is primarily focused on T lymphocyte-mediated inflammation/autoimmunity. Pain is a significant symptom associated with many musculoskeletal conditions leading to functional impairment and poor quality of life. While the role of IL-23 in arthritis has been studied in mouse models of adaptive immune-mediated arthritis using targeted approaches (e.g., monoclonal antibody (mAb) neutralization), the literature on IL-23 and arthritis pain is limited. Encouragingly, the anti-IL-23p19 mAb, guselkumab, reduces pain in psoriatic arthritis patients. Recent evidence has suggested a new biology for IL-23, whereby IL-23 is required in models of innate immune-mediated arthritis and its associated pain with its action being linked to a GM-CSF-dependent pathway (the so-called GM-CSF➔CCL17 pathway). This Commentary discusses the current understanding of potential cytokine networks involving IL-23 in arthritis pain and provides a rationale for future clinical studies targeting IL-23p19 in arthritis pain.

Arthritis and pain

Arthritic diseases, such as psoriatic arthritis (PsA) and rheumatoid arthritis (RA), are chronic inflammatory diseases, which impact patients both physically and psychologically. Neuropathic-like pain as evidence of abnormal pain processing is common in such patients [1, 2] and one of their highest priorities is chronic pain relief.

Nociception (pain) is the process by which chemical, mechanical or thermal stimuli are detected by specialized peripheral neurons called nociceptors [3]. During inflammation, the threshold for nociceptor neurons to fire action potentials is reduced by the triggering of key receptors, such as transient receptor potential vanilloid subfamily member 1 (TRPV1) and the sodium ion channel, Nav1.8 [4], leading to pain sensitivity or “hyperalgesia.” Studies are elucidating the role of specific immune cells and mediators in controlling pain sensitivity in different disease contexts. For example, in antigen-induced arthritis (AIA), macrophages have been observed to infiltrate both peripheral tissue (i.e., joints) and the dorsal root ganglion (DRG) [5, 6], and secreted cytokines, such as tumor necrosis factor (TNF), granulocyte macrophage-colony stimulating factor (GM-CSF) and CCL17, have been associated with inflammatory and arthritic pain development [5, 7]. Conversely, monocytes and macrophages can contribute to the resolution of inflammatory pain via a mechanism that is dependent on IL-10 signaling in DRGs [8, 9].

In this Commentary, we will focus on the role of IL-23 in regulating arthritis pain.

IL-23 in arthritis

IL-23 was discovered when a search for IL-6 cytokine family members identified the novel protein subunit, “p19” [10]. This protein is poorly secreted from cells but, when bound to the p40 subunit of IL-12, forms the secreted and bioactive cytokine, IL-23. A key role for IL-23 is to stimulate production of IL-17 from memory T cells [11], which were later termed Th17 cells [12]. While IL-23 acts late on adaptive T cells, it can act rapidly and directly on IL-23R-expressing innate-like lymphocytes, such as type 3 innate lymphoid cells [13].

IL-23p19 gene-deficient (Il23p19-/-) mice are protected from the development of collagen-induced arthritis (CIA) [14] and antigen-induced arthritis (AIA) [15]. Blocking IL-23 activity, using a neutralizing anti-IL-23p19 mAb following immunization [16, 17], but before disease onset, suppressed the severity of CIA [16]. In contrast, administration of the anti-IL-23p19 mAb following the first clinical signs of CIA gave no improvement [16]. These data suggest that IL-23 is required for disease onset but not for the effector phase of arthritis. There are clinical trial data indicating that anti-IL-23p19 mAb treatment met the primary endpoint (i.e., American College of Rheumatology 20% improvement) in PsA patients [18,19,20] but not in RA patients [21].

IL-23 and arthritis pain

Little is known about the role(s) of IL-23 in pathological pain development. However, it has been found in clinical trials that PsA patients receiving guselkumab (CNTO 1959, Janssen), a neutralizing mAb to IL-23p19, achieved both minimal disease activity, a composite index that includes the patient’s assessment of pain visual analog scale, and also significant improvements in the SF-36 physical component score, an assessment that includes bodily pain [18,19,20].

As regards experimental arthritis pain, it was reported recently, using the T cell-independent zymosan-induced arthritis (ZIA) and zymosan-induced paw inflammation models, that Il23p19-/- mice were protected from developing arthritis and inflammatory pain (i.e., weight bearing deficit), respectively [22]. Furthermore, it was found that Il23p19-/- mice were protected from GM-CSF-, TNF-, and CCL17-driven arthritis pain and disease [22], with these models also being T cell independent [23, 24]. Mechanistically, such protection in Il23p19-/- mice, at least when studied in the ZIA model, was found to correlate with reduced Csf2 (the gene encoding GM-CSF) and Ccl17 mRNA, but not Tnf mRNA, expression. Interestingly, in the ZIA joints, Il23p19 mRNA expression was found to be dependent on GM-CSF and TNF, but not on CCL17 [22]. These data suggest that the requirement for IL-23 in arthritis pain is associated with these inflammatory cytokines, with the responding cell(s) and/or the cellular source of IL-23 not being an adaptive T cell population(s). Conversely, direct injection of IL-23 in the plantar region induces inflammatory pain that also requires these cytokines as well as cyclooxygenase (COX) activity [22]. These findings provide the first evidence that the contribution of IL-23 to arthritis and inflammatory pain has potential links to TNF, GM-CSF, CCL17, and eicosanoid function. However, precisely how IL-23 contributes to arthritis pain development requires further study.

There are other mechanistic studies exploring how IL-23 can regulate pain. IL-23/IL-23 receptor (IL-23R) signaling in astrocytes has been implicated in central neuropathic pain in a model of sciatic nerve injury, and interaction between IL-23, CX3CL1, and IL-18 in the spinal cord was proposed [25]; also, IL-23-regulated T cell-derived cytokines, including possibly IL-17A, contribute to the inflammatory response in another model of neuropathic pain [26]. Interestingly, nociceptive sensory neurons can interact with dermal dendritic cells (DCs) to drive IL-23-mediated psoriasiform skin inflammation and resistance to cutaneous candidiasis [27, 28]. There is evidence for a link between the biologies of IL-23 and neuropeptides/neurotrophins, such as nerve growth factor (NGF) [29], calcitonin gene-related peptide (CGRP) [27, 28, 30] and substance P [31,32,33], all of which can be important mediators in pain development in humans [34] and have been implicated in inflammatory diseases of the skin (see, for example [35]). A recent study has demonstrated that IL-23 and IL-17A drive the crosstalk between immune cells (i.e., macrophages) and neurons for mechanical pain induction [36]. Additionally, cyclooxygenase products, such as prostaglandin E2, have been linked to IL-23 biology (see, for example, [37,38,39,40,41,42,43,44]).

IL-23 and arthritis pain: questions and issues

While there is some literature on the role of IL-23 in arthritis pain, several questions and issues which need to be addressed are as follows.

As mentioned, there are clinical trial data indicating that IL-23 blockade is effective in treating PsA [18,19,20], but not RA [21]. It would be interesting to know for which other arthritis patients IL-23 is important for their pain (and disease) and whether early and/or late IL-23p19 targeting would be effective. Also, there needs to be more research and clinical data on whether the beneficial effects of IL-23 blockade on pain are dependent or not on its effects on local inflammation.

There is evidence that pathological changes in the CNS, such as infiltration of immune cells, are also crucial components for maintaining chronic arthritis pain [6]. Although IL-23 biology is often associated with that of T lymphocytes in inflammation/autoimmunity, as outlined above, a recent study has demonstrated that IL-23 is required for different inflammatory arthritis pain models that exhibit lymphocyte-independent biology [22]. Little is known regarding the signficance of the role of lymphocyte-independent IL-23 biology in general, as well as for arthritis pain progression. More information is needed on which cell type(s) responds to IL-23 and which cell type(s) functions as its source. One possible responding cell type could be synovial fibroblasts as they have been shown to express IL-23R, and their activation by IL-23 can lead to TNF production [45].

For its involvement in arthritis pain, it is not known whether IL-23 can act peripherally and/or centrally. The current data on the effectiveness of systemic anti-IL-23p19 mAb administration in the control of arthritis pain [22] suggest perhaps that IL-23 is acting peripherally in the particular model studied. Given that IL-23 expression can be detected in DRGs [25, 46], it would be of interest to explore whether and, if so, how IL-23 can contribute to the activation of nociceptors for arthritis pain development.

We mentioned above that, in a recent study, IL-23 has been linked to the inflammatory cytokines/chemokines, TNF, GM-CSF, and CCL17, for the development of arthritis pain [22]. In a nerve injury model, an interaction between IL-23 and other cytokines/chemokines has been proposed [25], although the nature of these links is unknown. Which additional cytokines/chemokines may be critically linked with IL-23 in the regulation of arthritis pain are unknown. It is possible that there might not be a simple linear sequence of cytokine production and activity, but instead perhaps multiple mediator loops contributing to arthritis pain development [22]. It was also reported that neuropeptides/neurotrophins, namely NGF, CGRP, and substance P, are required for GM-CSF- and CCL17-driven inflammatory pain [47]. These mediators have been linked elsewhere with IL-23 biology [27,28,29,30,31,32,33] and exploring their link with IL-23 in arthritis pain would be worthwhile. The importance of other mediators (e.g., COX metabolites) in the action of IL-23 in arthritis pain remains to be determined.

This Commentary has focused mainly on IL-23 and its regulation of arthritis pain. How significant IL-23 generally is for the control of pain (and itch [48]) and how relevant are the IL-23-dependent mechanisms in arthritis pain to other conditions where pain is a debilitating symptom remain open areas for investigation. As an example, perhaps IL-23 may be contributing to the frequently reported abdominal pain in inflammatory bowel disease patients [49].

Conclusion

In contrast to the literature on lymphocyte-dependent IL-23 biology, it was recently reported that IL-23 is involved in innate immune-driven arthritis pain and disease with its links to other inflammatory cytokines, namely GM-CSF, CCL17, and TNF [22]. In this Commentary, we have mainly focused on the current understanding of the role of IL-23 in arthritis pain and the current evidence supporting its targeting for treating such pain. We have also listed a number of outstanding questions and issues that need to be addressed in order to advance our understanding of the role of IL-23 in arthritis pain.

Availability of data and materials

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Abbreviations

IL-23:

Interleukin-23

PsA:

Psoriatic arthritis

RA:

Rheumatoid arthritis

TRPV1:

Transient receptor potential vanilloid subfamily member 1

AIA:

Antigen-induced arthritis

GM-CSF:

Granulocyte macrophage-colony stimulating factor

TNF:

Tumor necrosis factor

CIA:

Collagen-induced arthritis

NGF:

Nerve growth factor

CGRP:

Calcitonin gene-related peptide

ZIA:

Zymosan-induced arthritis

COX:

Cyclooxygenase

DRG:

Dorsal root ganglion

IL-23R:

IL-23 receptor

DCs:

Dendritic cells

mAb:

Monoclonal antibody

References

  1. Ramjeeawon A, Choy E. Neuropathic-like pain in psoriatic arthritis: evidence of abnormal pain processing. Clin Rheumatol. 2019;38:3153–9.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Koop SM, ten Klooster PM, Vonkeman HE, Steunebrink LM, van de Laar MA. Neuropathic-like pain features and cross-sectional associations in rheumatoid arthritis. Arthritis Res Ther. 2015;17:237.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pinho-Ribeiro FA, Verri WA Jr, Chiu IM. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol. 2017;38:5–19.

    Article  CAS  PubMed  Google Scholar 

  5. Cook AD, Louis C, Robinson MJ, Saleh R, Sleeman MA, Hamilton JA. Granulocyte macrophage colony-stimulating factor receptor alpha expression and its targeting in antigen-induced arthritis and inflammation. Arthritis Res Ther. 2016;18:287.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Segond von Banchet G, Boettger MK, Fischer N, Gajda M, Brauer R, Schaible HG. Experimental arthritis causes tumor necrosis factor-alpha-dependent infiltration of macrophages into rat dorsal root ganglia which correlates with pain-related behavior. Pain. 2009;145:151–9.

    Article  CAS  PubMed  Google Scholar 

  7. Cook AD, Pobjoy J, Sarros S, Steidl S, Durr M, Lacey DC, et al. Granulocyte-macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain. Ann Rheum Dis. 2013;72:265–70.

    Article  CAS  PubMed  Google Scholar 

  8. Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 2009;6:e1000113.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Willemen HL, Eijkelkamp N, Garza Carbajal A, Wang H, Mack M, Zijlstra J, et al. Monocytes/macrophages control resolution of transient inflammatory pain. J Pain. 2014;15:496–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13:715–25.

    Article  CAS  PubMed  Google Scholar 

  11. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003;278:1910–4.

    Article  CAS  PubMed  Google Scholar 

  12. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Buonocore S, Ahern PP, Uhlig HH, Ivanov DR II, Littman KJ, Maloy, and F. Powrie. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature. 2010;464:1371–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198:1951–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cornelissen F, Mus AM, Asmawidjaja PS, van Hamburg JP, Tocker J, Lubberts E. Interleukin-23 is critical for full-blown expression of a non-autoimmune destructive arthritis and regulates interleukin-17A and RORgammat in gammadelta T cells. Arthritis Res Ther. 2009;11:R194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Cornelissen F, Asmawidjaja PS, Mus AM, Corneth O, Kikly K, Lubberts E. IL-23 dependent and independent stages of experimental arthritis: no clinical effect of therapeutic IL-23p19 inhibition in collagen-induced arthritis. PLoS One. 2013;8:e57553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yago T, Nanke Y, Kawamoto M, Furuya T, Kobashigawa T, Kamatani N, et al. IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats. Arthritis Res Ther. 2007;9:R96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Deodhar A, Helliwell PS, Boehncke WH, Kollmeier AP, Hsia EC, Subramanian RA, et al. Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFalpha inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395:1115–25.

    Article  CAS  PubMed  Google Scholar 

  19. Mease PJ, Rahman P, Gottlieb AB, Kollmeier AP, Hsia EC, Xu XL, et al. Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395:1126–36.

    Article  CAS  PubMed  Google Scholar 

  20. Mease P, Helliwell P, Gladman D, Poddubnyy D, Baraliakos X, Chakravarty S, et al. Efficacy of guselkumab, a monoclonal antibody that specifically binds to the p19 subunit of IL-23, on axial-related endpoints in patients with active PsA with imaging-confirmed sacroiliitis: week-52 results from two phase 3, randomized, double-blind, placebo-controlled studies [abstract]. Arthritis Rheumatol. 2020;72.

  21. Smolen JS, Agarwal SK, Ilivanova E, Xu XL, Miao Y, Zhuang Y, et al. A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. Ann Rheum Dis. 2017;76:831–9.

    Article  CAS  PubMed  Google Scholar 

  22. Lee KM, Zhang Z, Achuthan A, Fleetwood AJ, Smith JE, Hamilton JA, et al. IL-23 in arthritic and inflammatory pain development in mice. Arthritis Res Ther. 2020;22:123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Achuthan A, Cook AD, Lee MC, Saleh R, Khiew HW, Chang MW, et al. Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. J Clin Invest. 2016;126:3453–66.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cook AD, Lee MC, Saleh R, Khiew HW, Christensen AD, Achuthan A, et al. TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17. JCI Insight. 2018;3:e99249.

  25. Bian C, Wang ZC, Yang JL, Lu N, Zhao ZQ, Zhang YQ. Up-regulation of interleukin-23 induces persistent allodynia via CX3CL1 and interleukin-18 signaling in the rat spinal cord after tetanic sciatic stimulation. Brain Behav Immun. 2014;37:220–30.

    Article  CAS  PubMed  Google Scholar 

  26. Kleinschnitz C, Hofstetter HH, Meuth SG, Braeuninger S, Sommer C, Stoll G. T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression. Exp Neurol. 2006;200:480–5.

    Article  CAS  PubMed  Google Scholar 

  27. Riol-Blanco L, Ordovas-Montanes J, Perro M, Naval E, Thiriot A, Alvarez D, et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature. 2014;510:157–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kashem SW, Riedl MS, Yao C, Honda CN, Vulchanova L, Kaplan DH. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ Dermal Dendritic Cells and Drive Protective Cutaneous Immunity. Immunity. 2015;43:515–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Baerveldt EM, Onderdijk AJ, Kurek D, Kant M, Florencia EF, Ijpma AS, et al. Ustekinumab improves psoriasis-related gene expression in noninvolved psoriatic skin without inhibition of the antimicrobial response. Br J Dermatol. 2013;168:990–8.

    Article  CAS  PubMed  Google Scholar 

  30. Cohen JA, Edwards TN, Liu AW, Hirai T, Jones MR, Wu J, et al. Cutaneous TRPV1(+) neurons trigger protective innate type 17 anticipatory immunity. Cell. 2019;178:919–932 e914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vilisaar J, Kawabe K, Braitch M, Aram J, Furtun Y, Fahey AJ, et al. Reciprocal regulation of substance P and IL-12/IL-23 and the associated cytokines, IFNgamma/IL-17: a perspective on the relevance of this interaction to multiple sclerosis. J Neuroimmune Pharmacol. 2015;10:457–67.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Cunin P, Caillon A, Corvaisier M, Garo E, Scotet M, Blanchard S, et al. The tachykinins substance P and hemokinin-1 favor the generation of human memory Th17 cells by inducing IL-1beta, IL-23, and TNF-like 1A expression by monocytes. J Immunol. 2011;186:4175–82.

    Article  CAS  PubMed  Google Scholar 

  33. Blum A, Setiawan T, Hang L, Stoyanoff K, Weinstock JV. Interleukin-12 (IL-12) and IL-23 induction of substance p synthesis in murine T cells and macrophages is subject to IL-10 and transforming growth factor beta regulation. Infect Immun. 2008;76:3651–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sun S, Diggins NH, Gunderson ZJ, Fehrenbacher JC, White FA, Kacena MA. No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing. Bone. 2020;131:115109.

    Article  PubMed  CAS  Google Scholar 

  35. Choi JE, Di Nardo A. Skin neurogenic inflammation. Semin Immunopathol. 2018;40:249–59.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Luo X, Chen O, Wang Z, Bang S, Ji J, Lee SH, et al. IL-23/IL-17A/TRPV1 axis produces mechanical pain via macrophage-sensory neuron crosstalk in female mice. Neuron. 2021;109:2691–2706 e2695.

    Article  CAS  PubMed  Google Scholar 

  37. Sheibanie AF, Tadmori I, Jing H, Vassiliou E, Ganea D. Prostaglandin E2 induces IL-23 production in bone marrow-derived dendritic cells. FASEB J. 2004;18:1318–20.

    Article  CAS  PubMed  Google Scholar 

  38. Sheibanie AF, Khayrullina T, Safadi FF, Ganea D. Prostaglandin E2 exacerbates collagen-induced arthritis in mice through the inflammatory interleukin-23/interleukin-17 axis. Arthritis Rheum. 2007;56:2608–19.

    Article  CAS  PubMed  Google Scholar 

  39. Sheibanie AF, Yen JH, Khayrullina T, Emig F, Zhang M, Tuma R, et al. The proinflammatory effect of prostaglandin E2 in experimental inflammatory bowel disease is mediated through the IL-23-->IL-17 axis. J Immunol. 2007;178:8138–47.

    Article  CAS  PubMed  Google Scholar 

  40. Lemos HP, Grespan R, Vieira SM, Cunha TM, Verri WA Jr, Fernandes KS, et al. Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNgamma production. Proc Natl Acad Sci U S A. 2009;106:5954–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kalim KW, Groettrup M. Prostaglandin E2 inhibits IL-23 and IL-12 production by human monocytes through down-regulation of their common p40 subunit. Mol Immunol. 2013;53:274–82.

    Article  CAS  PubMed  Google Scholar 

  42. Boniface K, Bak-Jensen KS, Li Y, Blumenschein WM, McGeachy MJ, McClanahan TK, et al. Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. J Exp Med. 2009;206:535–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee J, Aoki T, Thumkeo D, Siriwach R, Yao C, Narumiya S. T cell-intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell-driven inflammation. J Allergy Clin Immunol. 2019;143:631–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shi Q, Yin Z, Zhao B, Sun F, Yu H, Yin X, et al. PGE2 elevates IL-23 production in human dendritic cells via a cAMP dependent pathway. Mediators Inflamm. 2015;2015:984690.

    PubMed  PubMed Central  Google Scholar 

  45. Gao J, Kong R, Zhou X, Ji L, Zhang J, Zhao D. Correction to: MiRNA-126 expression inhibits IL-23R mediated TNF-alpha or IFN-gamma production in fibroblast-like synoviocytes in a mice model of collagen-induced rheumatoid arthritis. Apoptosis. 2019;24:382.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Constantinescu CS, Tani M, Ransohoff RM, Wysocka M, Hilliard B, Fujioka T, et al. Astrocytes as antigen-presenting cells: expression of IL-12/IL-23. J Neurochem. 2005;95:331–40.

    Article  CAS  PubMed  Google Scholar 

  47. Lee KM, Jarnicki A, Achuthan A, Fleetwood AJ, Anderson GP, Ellson C, et al. CCL17 in inflammation and pain. J Immunol. 2020;205:213–22.

    Article  CAS  PubMed  Google Scholar 

  48. Pavlenko D, Funahashi H, Sakai K, Hashimoto T, Lozada T, Yosipovitch G, et al. IL-23 modulates histamine-evoked itch and responses of pruriceptors in mice. Exp Dermatol. 2020;29:1209–15.

    Article  CAS  PubMed  Google Scholar 

  49. Zeitz J, Ak M, Muller-Mottet S, Scharl S, Biedermann L, Fournier N, et al. Pain in IBD patients: very frequent and frequently insufficiently taken into account. PLoS One. 2016;11:e0156666.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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KMCL and JAH were supported by the University of Melbourne and grants from the National Health and Medical Research Council of Australia (NHMRC).

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KMCL, JPS, and JAH wrote, reviewed, and edited the manuscript. The author(s) read and approved the final manuscript.

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Lee, K.MC., Sherlock, J.P. & Hamilton, J.A. The role of interleukin (IL)-23 in regulating pain in arthritis. Arthritis Res Ther 24, 89 (2022). https://doi.org/10.1186/s13075-022-02777-y

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Keywords

  • IL-23
  • Arthritis
  • Pain and innate immunity