Bourcier Camille H, Michel-Flutot Pauline, Emam Laila, Adam Lucille, Gasser Adeline, Vinit Stéphane, Mansart Arnaud
END-ICAP, INSERM U1179, UVSQ-Université Paris-Saclay, Versailles, France.
Infection et Inflammation (2I), INSERM U1173, UVSQ-Université Paris-Saclay, Versailles, France.
Front Immunol. 2023 Sep 22;14:1228374. doi: 10.3389/fimmu.2023.1228374. eCollection 2023.
Severe inflammation via innate immune system activation causes organ dysfunction. Among these, the central nervous system (CNS) is particularly affected by encephalopathies. These symptoms are associated with the activation of microglia and a potential infiltration of leukocytes. These immune cells have recently been discovered to have the ability to produce extracellular traps (ETs). While these components capture and destroy pathogens, deleterious effects occur such as reduced neuronal excitability correlated with excessive ETs production. In this study, the objectives were to determine (1) whether immune cells form ETs in the CNS during acute inflammation (2) whether ETs produce neuromuscular disorders and (3) whether an immunomodulatory treatment such as β1-adrenergic blockers limits these effects. We observed an infiltration of neutrophils in the CNS, an activation of microglia and a production of ETs following lipopolysaccharide (LPS) administration. Atenolol, a β1-adrenergic blocker, significantly decreased the production of ETs in both microglia and neutrophils. This treatment also preserved the gastrocnemius motoneuron excitability. Similar results were observed when the production of ETs was prevented by sivelestat, an inhibitor of ET formation. In conclusion, our results demonstrate that LPS administration increases neutrophils infiltration into the CNS, activates immune cells and produces ETs that directly impair neuromuscular function. Prevention of ETs formation by β1-adrenergic blockers partly restores this function and could be a good target in order to reduce adverse effects in severe inflammation such as sepsis but also in other motor related pathologies linked to ETs production.
通过先天免疫系统激活引发的严重炎症会导致器官功能障碍。其中，中枢神经系统（CNS）特别容易受到脑病的影响。这些症状与小胶质细胞的激活以及白细胞的潜在浸润有关。最近发现这些免疫细胞具有产生细胞外陷阱（ETs）的能力。虽然这些成分捕获并破坏病原体，但也会产生有害影响，例如与过量ETs产生相关的神经元兴奋性降低。在本研究中，目标是确定：（1）在急性炎症期间免疫细胞是否在中枢神经系统中形成ETs；（2）ETs是否会导致神经肌肉疾病；（3）诸如β1 - 肾上腺素能阻滞剂之类的免疫调节治疗是否能限制这些影响。我们观察到在给予脂多糖（LPS）后，中枢神经系统中有中性粒细胞浸润、小胶质细胞激活以及ETs产生。阿替洛尔，一种β1 - 肾上腺素能阻滞剂，显著降低了小胶质细胞和中性粒细胞中ETs的产生。这种治疗还保留了腓肠肌运动神经元的兴奋性。当用西维来司他（一种ET形成抑制剂）阻止ETs产生时，观察到了类似的结果。总之，我们的结果表明，给予LPS会增加中性粒细胞向中枢神经系统的浸润，激活免疫细胞并产生直接损害神经肌肉功能的ETs。通过β1 - 肾上腺素能阻滞剂预防ETs形成可部分恢复此功能，并且可能是一个很好的靶点，以减少严重炎症（如败血症）以及其他与ETs产生相关的运动相关病理中的不良反应。
