Abstract：
Itaconate was initially identified as an antimicrobial compound produced by myeloid cells. Beyond its antimicrobial role, itaconate may also serve as a crucial metabolic and immune modulator. We therefore examined the roles of aconitate decarboxylase 1 (Acod1) and itaconate in house dust mite (HDM)-sensitized and -challenged mice, a model of T helper 2 (Th2)-driven allergic airways disease. HDM treatment induced lung Acod1 mRNA expression and bronchoalveolar lavage (BAL) itaconate levels in wild-type C57BL/6 mice. Acod1 knockout mice (Acod1-KO) with negligible BAL itaconate showed heightened HDM-induced type 2 cytokine expression, increased serum IgE, and enhanced recruitment of Th2 cells in the lung, indicating a shift towards a more pronounced Th2 immune response. Acod1-KO mice also showed increased eosinophilic airway inflammation and hyperresponsiveness. Experiments in chimeric mice demonstrated that bone marrow from Acod1-KO mice is sufficient to increase type 2 cytokine expression in wild-type mice, and that restitution of bone marrow from wild type mice attenuates mRNA expression of Th2 cytokines in Acod1-KO mice. Specific deletion of Acod1 in lysozyme-secreting macrophages (LysM-cre+Acod1flox/flox) recapitulated the exaggerated phenotype observed in whole-body Acod1-KO mice. Adoptive transfer of Acod1-KO bone marrow-derived macrophages also increased lung mRNA expression of Th2 cytokines. In addition, treatment of Th2-polarized CD4 cells with itaconate impeded Th2 cell differentiation, as shown by reduced expression of Gata3 and decreased release of IL-5 and IL-13. Finally, public datasets of human samples show lower Acod1 expression in subjects with allergic asthma, consistent with a protective role of itaconate in asthma pathogenesis. Together, these data suggest that itaconate plays a protective, immunomodulatory role in limiting airway type 2 inflammation after allergen challenge by attenuating T cell responses.
摘要：
衣糖酸最初被鉴定为由骨髓细胞产生的抗微生物化合物。除了它的抗菌作用，衣康酸酯还可以作为关键的代谢和免疫调节剂。因此，我们研究了乌头酸脱羧酶1（Acod1）和衣康酸在屋尘螨（HDM）致敏和攻击小鼠中的作用，T辅助细胞2（Th2）驱动的过敏性气道疾病模型。HDM处理在野生型C57BL/6小鼠中诱导肺Acod1mRNA表达和支气管肺泡灌洗(BAL)衣康酸水平。具有可忽略的BAL衣康酸的Acod1敲除小鼠（Acod1-KO）显示HDM诱导的2型细胞因子表达升高，血清IgE升高，增强了肺中Th2细胞的募集，表明向更明显的Th2免疫应答的转变。Acod1-KO小鼠也表现出增加的嗜酸性粒细胞气道炎症和高反应性。嵌合小鼠的实验表明，Acod1-KO小鼠的骨髓足以增加野生型小鼠的2型细胞因子表达，并且野生型小鼠骨髓的恢复减弱了Acod1-KO小鼠中Th2细胞因子的mRNA表达。溶菌酶分泌巨噬细胞（LysM-creAcod1flox/flox）中Acod1的特异性缺失概括了在全身Acod1-KO小鼠中观察到的夸大表型。Acod1-KO骨髓源性巨噬细胞的过继转移也增加了Th2细胞因子的肺mRNA表达。此外,用衣康酸处理Th2极化的CD4细胞阻碍Th2细胞分化，如Gata3的表达减少和IL-5和IL-13的释放减少所示。最后,人类样本的公共数据集显示，过敏性哮喘患者的Acod1表达较低，与衣康酸在哮喘发病机制中的保护作用一致。一起,这些数据表明，衣康酸起到保护作用，通过减弱T细胞反应限制过敏原攻击后气道2型炎症的免疫调节作用。
