Abstract The nervous and immune systems reciprocally regulate their functions through the release of chemical messengers. Norepinephrine (NE), a neurotransmitter released by catecholaminergic nerve endings, allows the sympathetic nervous system to communicate with immune cells through adrenergic receptors (ADR). We identified a novel role for the β2-ADR (ADRB2) in controlling inflammation. NE suppresses pro-inflammatory cytokine secretion from primary macrophages in response to multiple TLR agonists, and ADRB2 signaling enhances early induction of IL-10. We assessed the in vivo role of this pathway using a LPS endotoxemia model. ADRB2 −/− animals rapidly succumbed to a sub-lethal LPS challenge, which correlated with elevated serum levels of TNFα and reduced IL-10. The lethality in the ADRB2 −/− animals was rescued by administering exogenous IL-10. Additionally, the ADRB2-specific agonist salmeterol rescued wild-type animals from a lethal LPS challenge, which was reversed by neutralizing anti-IL-10 antibody. Additionally, ADRB2 −/− mice are unable to control inflammation models of infection and colitis. These observations suggest that ADRB2 signaling is critical for controlling inflammation through the rapid induction of IL-10. Through transcriptome analysis, the NR4A nuclear orphan family members were induced by NE, and the presence of several putative NR4A binding sites within the IL-10 promoter suggests that these factors may directly regulate IL-10 expression in response to ADRB2 signaling. Further studies will test the control of IL-10 expression by the NR4A family of transcription factors. Understanding this pathway will provide new insights into how the nervous and immune systems communicate through ADRB2 signaling.