Kupffer cell identity, phenotype, and function rely on continual hepatic sympathetic nerve output

Introduction/Rationale: Every organ in the body is innervated and contains populations of tissue-resident macrophages. Studies show communications between peripheral nerves and immunity in various organs; however, this is seldom explored in the liver. The liver is a firewall against bloodstream infection – a function made possible by Kupffer cells (KCs), the liver resident macrophage. Being uniquely situated in liver capillaries, KCs clear up to 95% of bacteria in the blood. Despite the liver being innervated, connections between hepatic nerves and KC are unclear. Here, we explore the interplay between hepatic nerves and KCs, hypothesizing that hepatic innervation is critical for KC identity, phenotype, and function.

Methods: We used tissue clearing to visualize the nerves in the liver. Intravital microscopy for assessing bacteria catching by KCs.

Results: We show that hepatic nerve fibers are primarily sympathetic nerves which line the portal vein of the liver but terminate before reaching the capillaries where KCs reside. This suggests that there is no direct physical interaction between KCs and hepatic sympathetic nerves. Despite this, sympathetic denervation reduced expression of genes associated with KC identity and led to reduced levels of receptors critical for KC function, like CRIg – a receptor required for catching bacteria. Sympathetic denervation significantly decreased bacteria catching by KCs, resulting in increased bacterial burden in the circulation and worse survival following bloodstream infection. Mechanistically, we show that liver-specific nerves release neurotransmitters and activate β-adrenergic receptors to maintain KC function and phenotype. Specific ablation of the β2-adrenergic receptor on KCs reduced bacteria catching suggesting that KCs directly sense neurotransmitters. Lastly, reintroducing norepinephrine into denervated mice rescued bacteria catching by KCs.

Conclusion: Overall, this study suggests that KC identity and function depend on norepinephrine released by hepatic sympathetic nerves.