van der Spek Anne H, Jim Kin Ki, Karaczyn Aldona, van Beeren Hermina C, Ackermans Mariëtte T, Darras Veerle M, Vandenbroucke-Grauls Christina M J E, Hernandez Arturo, Brouwer Matthijs C, Fliers Eric, van de Beek Diederik, Boelen Anita
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Endocrinology. 2018 Feb 1;159(2):826-835. doi: 10.1210/en.2017-00666.
Neutrophils are essential effector cells of the innate immune system that have recently been recognized as thyroid hormone (TH) target cells. Cellular TH bioavailability is regulated by the deiodinase enzymes, which can activate or inactivate TH. We have previously shown that the TH inactivating enzyme type 3 deiodinase (D3) is present in neutrophils. Furthermore, D3 knockout (D3KO) mice show impaired bacterial killing upon infection. We hypothesized that D3 plays a role in neutrophil function during infection by actively regulating local TH availability. We measured TH concentrations in cerebrospinal fluid (CSF) from patients with bacterial meningitis and controls. Bacterial meningitis resulted in marked changes in CSF TH levels, characterized by a strong increase of thyroxine and reverse-triiodothyronine concentrations. This altered TH profile was consistent with elevated D3 activity in infiltrating neutrophils at the site of infection. D3 knockdown in zebrafish embryos with pneumococcal meningitis resulted in increased mortality and reduced neutrophil infiltration during infection. Finally, stimulated neutrophils from female D3KO mice exhibited impaired NADPH-oxidase activity, an important component of the neutrophil bacterial killing machinery. These consistent findings across experimental models strongly support a critical role for reduced intracellular TH concentrations in neutrophil function during infection, for which the TH inactivating enzyme D3 appears essential.
中性粒细胞是先天性免疫系统的重要效应细胞，最近被确认为甲状腺激素（TH）的靶细胞。细胞内TH的生物利用度受脱碘酶调节，该酶可激活或失活TH。我们之前已表明，中性粒细胞中存在TH失活酶3型脱碘酶（D3）。此外，D3基因敲除（D3KO）小鼠在感染时细菌杀伤能力受损。我们推测，D3在感染期间通过积极调节局部TH的可利用性，在中性粒细胞功能中发挥作用。我们测量了细菌性脑膜炎患者和对照组脑脊液（CSF）中的TH浓度。细菌性脑膜炎导致CSF中TH水平发生显著变化，其特征是甲状腺素和反三碘甲状腺原氨酸浓度大幅升高。这种改变的TH谱与感染部位浸润的中性粒细胞中D3活性升高一致。在患有肺炎球菌性脑膜炎的斑马鱼胚胎中敲低D3会导致感染期间死亡率增加和中性粒细胞浸润减少。最后，来自雌性D3KO小鼠的受刺激中性粒细胞表现出NADPH氧化酶活性受损，NADPH氧化酶是中性粒细胞细菌杀伤机制的重要组成部分。这些在不同实验模型中的一致发现有力地支持了在感染期间细胞内TH浓度降低在中性粒细胞功能中起关键作用，而TH失活酶D3似乎对此至关重要。
