Irg1/itaconate metabolic pathway is a crucial determinant of dendritic cells immune-priming function and contributes to resolute allergen-induced airway inflammation.
Irg1/itaconate metabolic pathway is a crucial determinant of dendritic cells immune-priming function and contributes to resolute allergen-induced airway inflammation.
复制标题
DOI：
10.1038/s41385-021-00462-y
复制
发表时间：
2022-03
影响因子：
8
通讯作者：
Mishra A
中科院分区：
文献类型：
--
作者：
Jaiswal AK;Yadav J;Makhija S;Mazumder S;Mitra AK;Suryawanshi A;Sandey M;Mishra A
衣康酸是由线粒体TCA循环酶乌头酸酶脱羧酶(由免疫反应基因1编码；IRG1编码)产生的，在髓系细胞中发挥免疫调节功能。然而，IRG1/衣康酸通路在树突状细胞(DC)介导的呼吸道炎症和对吸入性变应原的适应性免疫中的作用仍不清楚，而吸入性变应原是过敏性哮喘的主要抗原提呈细胞。屋尘螨(HDM)攻击的−/−小鼠表现出嗜酸性呼吸道炎症、粘液细胞化生和Th2型细胞因子的增加，其机制与DC呈递尘螨抗原有关。过继地将IRG1缺陷小鼠的HDM冲击的DC转移到幼稚的WT小鼠中，诱导了类似的2型呼吸道炎症和过敏性致敏的表型。对HDM冲击的DC的非靶向代谢物分析显示，衣康酸是可能抑制线粒体氧化损伤的最丰富的极性代谢物之一。此外，衣康酸的免疫调节作用是体内翻译的，其中4-辛基衣康酸4-OI在抗原预充后鼻腔给药可减轻HDM诱导的呼吸道疾病和Th2免疫反应的表现。综上所述，这些数据首次证明了树突状细胞中IRG1/衣康酸途径在2型呼吸道炎症发展中的直接调节作用，并提示了调节过敏性哮喘的可能治疗靶点。
Itaconate is produced from the mitochondrial TCA cycle enzyme aconitase decarboxylase (encoded by immune responsive gene1; Irg1) that exerts immunomodulatory function in myeloid cells. However, the role of the Irg1/itaconate pathway in dendritic cells (DC)-mediated airway inflammation and adaptive immunity to inhaled allergens, which are the primary antigen-presenting cells in allergic asthma, remains largely unknown. House dust mite (HDM)-challenged Irg1−/− mice displayed increases in eosinophilic airway inflammation, mucous cell metaplasia, and Th2 cytokine production with a mechanism involving impaired mite antigen presentations by DC. Adoptive transfer of HDM-pulsed DC from Irg1-deficient mice into naïve WT mice induced a similar phenotype of elevated type 2 airway inflammation and allergic sensitization. Untargeted metabolite analysis of HDM-pulsed DC revealed itaconate as one of the most abundant polar metabolites that potentially suppress mitochondrial oxidative damage. Furthermore, the immunomodulatory effect of itaconate was translated in vivo, where intranasal administration of 4-octyl itaconate 4-OI following antigen priming attenuated the manifestations of HDM-induced airway disease and Th2 immune response. Taken together, these data demonstrated for the first time a direct regulatory role of the Irg1/itaconate pathway in DC for the development of type 2 airway inflammation and suggest a possible therapeutic target in modulating allergic asthma.
登录
查看更多内容
影响因子：
11.4
作者：
Hough KP;Trevor JL;Strenkowski JG;Wang Y;Chacko BK;Tousif S;Chanda D;Steele C;Antony VB;Dokland T;Ouyang X;Zhang J;Duncan SR;Thannickal VJ;Darley-Usmar VM;Deshane JS
通讯作者：
Deshane JS
影响因子：
29
作者：
Hooftman, Alexander;Angiari, Stefano;O'Neill, Luke A. J.
通讯作者：
O'Neill, Luke A. J.
影响因子：
20.3
作者：
Everts, Bart;Amiel, Eyal;Pearce, Edward J.
通讯作者：
Pearce, Edward J.
影响因子：
6.4
作者：
Butler, Matt;Morel, Anne-Sophie;Ritter, Mary A.
通讯作者：
Ritter, Mary A.
影响因子：
82.9
作者：
通讯作者：
--