Dysfunction of cholinergic neuron in nucleus ambiguous aggravates sepsis-induced lung injury via a GluA1-dependment...

Clinical and neuropathological observations suggest that patients with sepsis may have brainstem autonomic dysfunction. However, the influence of peripheral inflammation on vagal preganglionic neurons is poorly understood. Our hypothesis is that sepsis-induced central vagus dysfunction affects the cholinergic anti-inflammatory pathway and consequently contributes to respiratory failure. Here, we identified neuron apoptosis in the nucleus ambiguus (NA) after sepsis; NA is not only a component of the efferent arm of the inflammatory reflex but also plays an important role in respiratory regulation. Conditional ablation of cholinergic neurons in the NA leads to a decrease in vagus nerve firing, significant impairment of respiratory function, and inflammatory changes in lung tissues. The accumulation of glutamate and increased expression of Ca²⁺-permeable (CP)-AMPA receptors (AMPARs) mediated the excitotoxicity of NA neurons. Microinjection of IEM1460 (a selective blocker of GluA2- lacking AMPARs) partly rescued vagus firing and respiratory function in mice with sepsis. We showed that peripheral sepsis caused brainstem inflammation and impaired the cholinergic anti-inflammatory pathway after infection. We conclude that central efferent vagus dysfunction may impact vital organ systems in sepsis.