Korhonen Paula, Pollari Eveliina, Kanninen Katja M, Savchenko Ekaterina, Lehtonen Šárka, Wojciechowski Sara, Pomeshchik Yuriy, Van Den Bosch Ludo, Goldsteins Gundars, Koistinaho Jari, Malm Tarja
A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
KU Leuven, University of Leuven, Department of Neurosciences, Experimental Neurology, VIB Center for Brain & Disease Research, Box 912, B-3000 Leuven, Belgium.
IBRO Rep. 2019 Jan 11;6:74-86. doi: 10.1016/j.ibror.2019.01.005. eCollection 2019 Jun.
Inflammation is a prominent feature of the neuropathology of amyotrophic lateral sclerosis (ALS). Emerging evidence suggests that inflammatory cascades contributing to the disease progression are not restricted to the central nervous system (CNS) but also occur peripherally. Indeed, alterations in T cell responses and their secreted cytokines have been detected in ALS patients and in animal models of ALS. One key cytokine responsible for the shift in T cell responses is interleukin-33 (IL-33), which stimulates innate type 2 immune cells to produce a large amount of Th2 cytokines that are possibly beneficial in the recovery processes of CNS injuries. Since the levels of IL-33 have been shown to be decreased in patients affected with ALS, we sought to determine whether a long-term recombinant IL-33 treatment of a transgenic mouse model of ALS expressing G93A-superoxide dismutase 1 (SOD1-G93A) alters the disease progression and ameliorates the ALS-like disease pathology. SOD1-G93A mice were treated with intraperitoneal injections of IL-33 and effects on disease onset and inflammatory status were determined. Spinal cord (SC) neurons, astrocytes and T-cells were exposed to IL-33 to evaluate the cell specific responses to IL-33. Treatment of SOD1-G93A mice with IL-33 delayed the disease onset in female mice, decreased the proportion of CD4+ and CD8 + T cell populations in the spleen and lymph nodes, and alleviated astrocytic activation in the ventral horn of the lumbar SC. Male SOD1-G93A mice were unresponsive to the treatment. In vitro studies showed that IL-33 is most likely not acting directly on neurons and astrocytes, but rather conveying its effects through peripheral T-cells. Our results suggest that strategies directed to the peripheral immune system may have therapeutic potential in ALS. The effect of gender dimorphisms to the treatment efficacy needs to be taken into consideration when designing new therapeutic strategies for CNS diseases.
炎症是肌萎缩侧索硬化症（ALS）神经病理学的一个显著特征。新出现的证据表明，促成疾病进展的炎症级联反应不仅局限于中枢神经系统（CNS），在外周也会发生。事实上，在ALS患者和ALS动物模型中已检测到T细胞反应及其分泌的细胞因子的改变。导致T细胞反应转变的一种关键细胞因子是白细胞介素-33（IL-33），它刺激固有2型免疫细胞产生大量Th2细胞因子，这些细胞因子可能对CNS损伤的恢复过程有益。由于已证明ALS患者体内IL-33水平降低，我们试图确定长期用重组IL-33治疗表达G93A-超氧化物歧化酶1（SOD1-G93A）的ALS转基因小鼠模型是否会改变疾病进展并改善ALS样疾病病理学。对SOD1-G93A小鼠进行腹腔注射IL-33治疗，并确定其对疾病发作和炎症状态的影响。将脊髓（SC）神经元、星形胶质细胞和T细胞暴露于IL-33中，以评估细胞对IL-33的特异性反应。用IL-33治疗SOD1-G93A小鼠可延迟雌性小鼠的疾病发作，降低脾脏和淋巴结中CD4+和CD8+T细胞群体的比例，并减轻腰段脊髓腹角的星形胶质细胞活化。雄性SOD1-G93A小鼠对该治疗无反应。体外研究表明，IL-33很可能不是直接作用于神经元和星形胶质细胞，而是通过外周T细胞传递其作用。我们的结果表明，针对外周免疫系统的策略可能对ALS具有治疗潜力。在设计中枢神经系统疾病的新治疗策略时，需要考虑性别差异对治疗效果的影响。
