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<p>Itaconate (ITA) originates by decarboxylation of cis-aconitate catalyzed by the enzyme aconitate decarboxylase 1. It has immunomodulatory properties, but its role in T cells, especially CD4<sup>+</sup> T cells, is mostly unexplored. Here, we examined the effects of ITA and its derivatives 4-octyl itaconate (4-OI) and dimethyl itaconate (DMI) on CD4<sup>+</sup> T cells. We demonstrate that itaconate, 4-OI, and DMI specifically inhibit Th17 cells differentiation under cell-polarizing conditions, reduce IL-17&#xa0;A secretion and mRNA expression of Th17 cell-related genes including <i>Il17a</i>, <i>Il22</i> and <i>Il17f.</i> Metabolic profiling, [U-<sup>13</sup>C<sub>5</sub>]-itaconate tracking, and metabolite supplementation studies indicated that Th17 cells uptake ITA through SLC16A1/3 transporters, and exogenous ITA affects amino acid metabolism and oxidative phosphorylation in Th17 cells. Mechanistically, itaconate, 4-OI, and DMI affect mitochondrial quality, reduce mitochondrial membrane potential, lower cellular potential for mitophagy, and mitophagy inducer P62-mediated mitophagy inducer (PMI) can rescue inhibitory effects of itaconate, 4-OI, and DMI on Th17 cells. In vivo, 4-OI treatment suppresses Th17 cells frequency and ameliorates autoimmune disease, imiquimod-induced psoriasis. Our findings reveal itaconate and its derivatives as specific negative regulators of Th17-type response, and ITA-dependent mechanisms as a potential therapy in autoimmune diseases.</p>

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Itaconate and its derivatives ameliorate autoimmunity by suppressing Th17 cells via regulating mitophagy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月22日

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  • Fuli Li,
  • Qing Huang,
  • Naisheng Zheng,
  • Wenyu Zhang,
  • Shan Luo,
  • Ruowen Wang,
  • Thulasiram Bathini,
  • Pengkai Sun,
  • Xinjian Li,
  • Xian Huang,
  • Tomasz Maj

摘要

Itaconate (ITA) originates by decarboxylation of cis-aconitate catalyzed by the enzyme aconitate decarboxylase 1. It has immunomodulatory properties, but its role in T cells, especially CD4+ T cells, is mostly unexplored. Here, we examined the effects of ITA and its derivatives 4-octyl itaconate (4-OI) and dimethyl itaconate (DMI) on CD4+ T cells. We demonstrate that itaconate, 4-OI, and DMI specifically inhibit Th17 cells differentiation under cell-polarizing conditions, reduce IL-17 A secretion and mRNA expression of Th17 cell-related genes including Il17a, Il22 and Il17f. Metabolic profiling, [U-13C5]-itaconate tracking, and metabolite supplementation studies indicated that Th17 cells uptake ITA through SLC16A1/3 transporters, and exogenous ITA affects amino acid metabolism and oxidative phosphorylation in Th17 cells. Mechanistically, itaconate, 4-OI, and DMI affect mitochondrial quality, reduce mitochondrial membrane potential, lower cellular potential for mitophagy, and mitophagy inducer P62-mediated mitophagy inducer (PMI) can rescue inhibitory effects of itaconate, 4-OI, and DMI on Th17 cells. In vivo, 4-OI treatment suppresses Th17 cells frequency and ameliorates autoimmune disease, imiquimod-induced psoriasis. Our findings reveal itaconate and its derivatives as specific negative regulators of Th17-type response, and ITA-dependent mechanisms as a potential therapy in autoimmune diseases.