IL-27 Counteracts Neuropathic Pain Development Through Induction of IL-10

Abstract

Neuroimmune-glia interactions have been implicated in the development of neuropathic pain. Interleukin-27 (IL-27) is a cytokine that presents regulatory activity in inflammatory conditions of the central nervous system. Thus, we hypothesized that IL-27 would participate in the neuropathic pain process. Here, we found that neuropathic pain caused by peripheral nerve injury (spared nerve injury model; SNI), was enhanced in IL-27-deficient (−/−) mice, whereas nociceptive pain is similar to that of wild-type mice. SNI induced an increase in the expression of IL-27 and its receptor subunit (Wsx1) in the sensory ganglia and spinal cord. IL-27 receptor was expressed mainly in resident macrophage, microglia, and astrocytes of the sensory ganglia and spinal cord, respectively. Finally, we identify that the antinociceptive effect of IL-27 was not observed in IL-10 −/− mice. These results provided evidence that IL-27 is a cytokine produced after peripheral nerve injury that counteracts neuropathic pain development through induction of the antinociceptive cytokine IL-10. In summary, our study unraveled the role of IL-27 as a regulatory cytokine that counteracts the development of neuropathic pain after peripheral nerve damage. In conclusion, they indicate that immunotherapies based on IL-27 could emerge as possible therapeutic approaches for the prevention of neuropathic pain development after peripheral nerve injury.

Sensory neuron–associated macrophages as novel modulators of neuropathic pain

“…For instance, we recently found that at the level of sensory ganglia there is an increase in the production of IL-27 which plays a regulatory role in the development of neuropathic pain. 52 We also showed that Il-27 counteracts neuropathic pain by acting on its receptor expressed by sNAMs that in turn stimulate the production of the antinociceptive cytokine IL-10. 52 …”

“…Concomitantly to the production of pronociceptive molecules by immune and glial cells across the pain pathway (local of injury; sensory ganglia, and spinal cord) after peripheral nerve injury, there is also evidence suggesting the production of anti-inflammatory/antinociceptive molecules. 3 , 5 , 14 , 20 , 22 , 52 , 85 , 144 , 145 , 168 , 229 In this context, increasing evidence suggests that peripheral macrophages also play an important role in the resolution of chronic pain. 25 , 39 The identification of these regulatory mechanisms in peripheral macrophages that counteract neuropathic pain would also reveal novel targets for its treatment.…”

Neuroinflammation in HIV-Related Neuropathic Pain

“…Reversely, M2 macrophages produce antiinflammatory cytokine IL-10. The enhancement of IL-10 expression or inhibition of M1 macrophages could attenuate or abolish the neuropathic pain state (Kiguchi et al, 2017;Fonseca et al, 2019;Iwasa et al, 2019). Schwann cells are important glial cells in the peripheral nervous system, which act as insulators of axons.…”

“…Actually, immune cells express inflammation modulatory factors (e.g., IL-10 and IL-27) during different phases of HIV infection (Soare et al, 2019). IL-27 receptor, expressed by macrophage, microglia, and astrocytes of the sensory ganglia and spinal cord, its activation has the function of counteracting neuropathic pain (Fonseca et al, 2019). Therefore, both pro-inflammation and anti-inflammation are processing simultaneously between immune cells.…”

Novel Analgesics with Peripheral Targets

“…IL-27 and IL-35 are structurally different (heterodimeric cytokines) to the original members, however still considered a part of the IL-6 superfamily. Genetic ablation of IL-27 was shown to deprive mice of an innate IL-10-dependent antinociceptive reaction in a nerve injury model [ 664 ]. IL-27 acts anti-inflammatory, limiting thermal and mechanical sensation, as mice lacking IL-27 or its receptor spontaneously showed chronic pain-like hypersensitivity, with reversal of the behaviors upon recombinant IL-27 injection [ 665 ].…”