Sympathetic Norepinephrine Modulates Inflammatory Activation in Intestinal Muscularis Resident Macrophages via Beta1‐Adrenergic Receptors

BACKGROUND: Intestinal muscularis resident macrophages (MMφ) are a specialized subset of tissue macrophages involved in local inflammatory regulation. Although sympathetic nerves are anatomically associated with MMφ, the mechanisms underlying their interaction remain unclear. This study aimed to elucidate the role of adrenergic receptor signaling in modulating MMφ activation during lipopolysaccharide (LPS)-induced inflammation. METHODS: MMφ were isolated from mouse intestinal muscularis for receptor profiling. The macrophage-like cell line J774.1 was stimulated with LPS, with or without adrenergic modulators. LPS-treated intestinal segments were examined ex vivo under electrical stimulation with sympathetic or β-adrenergic blockade. Macrophage activation was assessed by measuring nitric oxide (NO) production and iNOS mRNA expression. KEY RESULTS: MMφ isolated from mouse muscularis expressed α₁, α₂, β₁, and β₂ adrenergic receptors. In J774.1 cells, LPS significantly increased NO production. Activation of α₁, β₁, or β₂ receptors attenuated this response, whereas α₂ activation enhanced it. Norepinephrine similarly suppressed LPS-induced NO increase, and this suppression was reversed by β₁/β₂ antagonists. Inhibition of adenylate cyclase also reversed the NO suppression induced by a non-selective β receptor agonist. In intestinal segments, LPS-induced iNOS expression was not altered by electrical stimulation, but was significantly enhanced when stimulation was combined with non-selective β or β₁ antagonists. CONCLUSIONS AND INFERENCES: Our results suggest that norepinephrine released from sympathetic nerves suppresses inflammation via activation of β₁ and β₂ receptors on MMφ. These findings advance the understanding of neuroimmune interactions underlying gastrointestinal homeostasis and its disruption during inflammatory states.