IRG1/itaconate increases IL-10 release to alleviate mechanical and thermal hypersensitivity in mice after nerve injury

Abstract

Inflammation plays an important role in the occurrence and development of neuropathic pain. Immune-responsive gene 1 (IRG1) decarboxylates cis-aconitate to produce itaconate in the mitochondria. Itaconate serves as an immunomodulator of macrophages and represses inflammation in infectious diseases. Recently, a study showed that an itaconate derivative inhibits neuroinflammation and reduces chronic pain in mice. However, the function and molecular mechanisms of endogenous itaconate in neuropathic pain have not been fullyelucidated. In this study, the content of itaconate in the ipsilateral spinal cord after nerve-injured mice was detected with mass spectrometry. The Irg1-/- mouse was constructed to determine the role of endogenous itaconate in the chronic constriction nerve injury (CCI) model. The analgesic effect of exogenous itaconate was assessed with intraperitoneal and intrathecal administration in both male and female CCI mice. The spinal application of 4-OI also reduced the evoked responses of wide dynamic range neurons in CCI mice. The potential analgesic mechanism of itaconate was explored through molecular biology experiments and verified in Interleukin (IL)-10-/- mice. We found the levels of itaconate and IRG1 in the spinal cord significantly increased after CCI. Irg1 deficiency aggravated the mechanical and heat hypersensitivity, while the exogenous administration of the itaconate derivative 4-OI alleviated the neuropathic pain in male and female CCI mice. Mechanistically, the treatment of 4-OI increased the level of IL-10 and activates STAT3/β-endorphin pathway in the spinal cord, and the analgesia effect of itaconate was impaired in IL-10-/- mice. Finally, we showed that the upregulation of IL-10 induced by 4-OI was mainly from spinal neurons through Nrf2 pathway. This study demonstrated the analgesic effect of endogenous and exogenous itaconate in the neuropathic pain model, suggesting that the spinal IL-10/STAT3/β-endorphin pathway might mediate the analgesia effect of itaconate.

The potential role of T-cell metabolism-related molecules in chronic neuropathic pain after nerve injury: a narrative review

“…In studies of neuropathic pain resulting from peripheral nerve injury in mice, CD8 + T lymphocytes aggregate to a greater extent in the DRG and dorsal horn by migration after CCI, yet infiltrate mainly in the ventral horn after transection. These cells have been found to produce IL-10, which can relieve chronic pain ( 33 ), indicating that they may play a role in the resolution of chronic pain. However, it is worth noting that CD8 + T cells are not the only source of IL-10, as CD4 + T cells and macrophages are also capable of producing this cytokine ( 34 ).…”

Itaconate as a key regulator of respiratory disease

“…In addition, itaconate can exhibit anti-inflammatory functions via NRF2-independent pathways. In the context of neuropathic pain, itaconate has been shown to promote IL-10 production [ 23 ]. LPS can induce the expression of Tnf and Nfkbiz via activation of TLRs independent of NRF2 [ 24 ].…”

IL-10/β-Endorphin-Mediated Neuroimmune Modulation on Microglia during Antinociception

“…Furthermore, a theme that has been growing in recent years is how immunometabolic processes act on the functionality of the immunological component. Sun and colleagues [57] checked that itaconate, a metabolite arising from the tricarboxylic acid cycle (TCA) [58] commonly secreted after macrophage activation through the enzyme cis-aconitate decar-boxylase 1 (IRG1), can mediate the analgesic effect in chronic constrictive nerve injury (CCI) mouse models via IL-10/STAT3/β-endorphin. IRG1 deficient mice showed greater mechanical and heat hypersensitivity.…”

“…In this model, neuropathic pain was relieved after itaconate administration. Interestingly, this effect was impaired in IL-10 knockout mice, demonstrating that itaconate treatment increased IL-10 and β-endorphin levels, which were especially secreted by spinal neurons, a process whose microglia involvement still needs to be investigated [57]. Thus, approaches that assess the immunometabolic impact on microglia and its reflection on IL-10/β-endorphin-mediated neuroimmune modulation may become a key point to elucidate and propose new studies and therapeutic models aimed at combating pain.…”