Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States.
Department of Genetics, Pediatrics and Neuroscience, Yale University School of Medicine, New Haven, CT, United States.
Front Immunol. 2023 Feb 8;14:1124356. doi: 10.3389/fimmu.2023.1124356. eCollection 2023.
Excessive inflammation has been implicated in autism spectrum disorder (ASD), but the underlying mechanisms have not been fully studied. SHANK3 is a synaptic scaffolding protein and mutations of are involved in ASD. Shank3 expression in dorsal root ganglion sensory neurons also regulates heat pain and touch. However, the role of Shank3 in the vagus system remains unknown. We induced systemic inflammation by lipopolysaccharide (LPS) and measured body temperature and serum IL-6 levels in mice. We found that homozygous and heterozygous deficiency, but not and deficiency, aggravates hypothermia, systemic inflammation (serum IL-6 levels), and sepsis mortality in mice, induced by lipopolysaccharide (LPS). Furthermore, these deficits can be recapitulated by specific deletion of in Nav1.8-expressing sensory neurons in conditional knockout (CKO) mice or by selective knockdown of or in vagal sensory neurons in nodose ganglion (NG). Mice with deficiency have normal basal core temperature but fail to adjust body temperature after perturbations with lower or higher body temperatures or auricular vagus nerve stimulation. hybridization with RNAscope revealed that is broadly expressed by vagal sensory neurons and this expression was largely lost in cKO mice. Mechanistically, regulates the expression of in NG, as but not mRNA levels in NG were significantly reduced in KO mice. Our findings demonstrated a novel molecular mechanism by which Shank3 in vagal sensory neurons regulates body temperature, inflammation, and sepsis. We also provided new insights into inflammation dysregulation in ASD.
过度炎症与自闭症谱系障碍（ASD）有关，但潜在机制尚未完全研究。SHANK3 是一种突触支架蛋白， 突变与 ASD 有关。Shank3 在背根神经节感觉神经元中的表达也调节热痛和触觉。然而，Shank3 在迷走神经系统中的作用尚不清楚。我们通过脂多糖（LPS）诱导全身性炎症，并测量小鼠的体温和血清 IL-6 水平。我们发现， 纯合和杂合 缺陷，但不是 和 缺陷，加剧了 LPS 诱导的小鼠低体温、全身炎症（血清 IL-6 水平）和败血症死亡率。此外，这些缺陷可以通过在条件性敲除（CKO）小鼠中特异性缺失 Nav1.8 表达的感觉神经元中的 或通过选择性敲低迷走神经节（NG）中的 或 来重现。 缺陷小鼠的基础核心体温正常，但在体温较低或较高或耳迷走神经刺激后无法调节体温。RNAscope 杂交显示 广泛表达于迷走感觉神经元，而在 cKO 小鼠中这种表达大部分丢失。从机制上讲， 调节 NG 中 的表达，因为在 KO 小鼠中 NG 中的 而不是 mRNA 水平显著降低。我们的发现展示了 Shank3 在迷走感觉神经元中调节体温、炎症和败血症的新分子机制。我们还为 ASD 中的炎症失调提供了新的见解。
