Seshadri Sudarshan, Allan David S J, Carlyle James R, Zenewicz Lauren A
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
PLoS Pathog. 2017 Oct 23;13(10):e1006690. doi: 10.1371/journal.ppat.1006690. eCollection 2017 Oct.
Bacillus anthracis, the causative agent of anthrax, secretes lethal toxin that down-regulates immune functions. Translocation of B. anthracis across mucosal epithelia is key for its dissemination and pathogenesis. Group 3 innate lymphocytes (ILC3s) are important in mucosal barrier maintenance due to their expression of the cytokine IL-22, a critical regulator of tissue responses and repair during homeostasis and inflammation. We found that B. anthracis lethal toxin perturbed ILC3 function in vitro and in vivo, revealing an unknown IL-23-mediated MAPK signaling pathway. Lethal toxin had no effects on the canonical STAT3-mediated IL-23 signaling pathway. Rather lethal toxin triggered the loss of several MAP2K kinases, which correlated with reduced activation of downstream ERK1/2 and p38, respectively. Inhibition studies showed the importance of MAPK signaling in IL-23-mediated production of IL-22. Our finding that MAPK signaling is required for optimal IL-22 production in ILC3s may lead to new approaches for targeting IL-22 biology.
炭疽芽孢杆菌是炭疽病的病原体，可分泌下调免疫功能的致死毒素。炭疽芽孢杆菌跨黏膜上皮细胞的转运是其传播和致病的关键。3型天然淋巴细胞（ILC3s）因其表达细胞因子IL-22而在维持黏膜屏障中起重要作用，IL-22是稳态和炎症期间组织反应及修复的关键调节因子。我们发现炭疽芽孢杆菌致死毒素在体外和体内扰乱了ILC3的功能，揭示了一条未知的IL-23介导的MAPK信号通路。致死毒素对经典的STAT3介导的IL-23信号通路没有影响。相反，致死毒素引发了几种MAP2K激酶的缺失，这分别与下游ERK1/2和p38的激活减少相关。抑制研究表明MAPK信号在IL-23介导的IL-22产生中的重要性。我们发现MAPK信号是ILC3s中最佳产生IL-22所必需的，这一发现可能会带来针对IL-22生物学特性的新方法。
