Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Cytokine. 2022 May;153:155862. doi: 10.1016/j.cyto.2022.155862. Epub 2022 Mar 17.
Group 3 innate lymphocytes (ILC3s) are important immune cells within mucosal tissues and protect against bacterial infections. They can be activated in response to the innate cytokines IL-23 or IL-1β, which rapidly increases their production of effector molecules that regulate barrier functions. Pathogens can subvert these anti-bacterial effects to evade mucosal defenses to infect the host. Bacillus anthracis, the causative agent of anthrax, produces two major toxins that can modulate the immune response. We have previously shown that lethal toxin downmodulates the function of ILC3s. On the other hand, edema toxin has been shown promote T helper 17 (Th17) cell differentiation, adaptive counterparts of ILC3s, via elevation of cyclic adenosine monophosphate (cAMP). We hypothesized that edema toxin may also modulate ILC3 function. In this study, we show that edema toxin has the opposite effect of lethal toxin; edema toxin directly activates ILC3s independently of innate cytokine stimulation. Treatment of a mouse ILC3-like cell line with edema toxin, a potent adenylate cyclase, upregulated production of the cytokine IL-22, a major effector molecule of ILC3s and a critical factor in maintaining mucosal barriers. Forskolin treatment phenocopied the effect observed with edema toxin and led to an increase in CREB phosphorylation in ILC3s. This observation has potential implications for a role for cAMP signaling in the activation of ILC3s.
第三组固有淋巴细胞 (ILC3) 是黏膜组织中重要的免疫细胞，可抵抗细菌感染。它们可以响应先天细胞因子 IL-23 或 IL-1β 被激活，这会迅速增加它们调节屏障功能的效应分子的产生。病原体可以颠覆这些抗细菌作用，从而逃避黏膜防御以感染宿主。炭疽芽孢杆菌是炭疽病的病原体，它产生两种主要的毒素，可以调节免疫反应。我们之前已经表明致死毒素下调了 ILC3 的功能。另一方面，水肿毒素已被证明通过提高环磷酸腺苷 (cAMP) 促进 T 辅助 17 (Th17) 细胞分化，即 ILC3 的适应性对应物。我们假设水肿毒素也可能调节 ILC3 的功能。在这项研究中，我们表明水肿毒素具有与致死毒素相反的作用；水肿毒素可直接激活 ILC3，而无需先天细胞因子刺激。用水肿毒素（一种有效的腺苷酸环化酶）处理一种类似于小鼠 ILC3 的细胞系，上调了细胞因子 IL-22 的产生，IL-22 是 ILC3 的主要效应分子，也是维持黏膜屏障的关键因素。福司可林处理模拟了水肿毒素观察到的效果，并导致 ILC3 中 CREB 磷酸化增加。这一观察结果可能表明 cAMP 信号在 ILC3 的激活中起作用。
