Sympathetic Neural Control of Inflammation by ADRB2-Mediated IL-10 Secretion

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). Although, the effects of adrenergic signaling has been studied in multiple cell types, its role in modulation of innate immune cells is relatively unknown. Here, I demonstrate a novel role for the beta2-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. In addition to its in vitro affects, I have shown that ADRB2 signaling controls inflammation in vivo. The in vivo role of this pathway was assessed by using an infection model, experimental colitis and LPS endotoxemia model. ADRB2-/- animals presented with splenomegaly and greater weight loss in infection and colitis, compared to ADRB2 sufficient animals, respectively. ADRB2-/- animals rapidly succumbed to a sub-lethal LPS challenge, which correlated with elevated serum levels of TNFα and reduced IL-10. Administration of exogenous IL-10 increased the survival of the ADRB2-/-. Additionally, the ADRB2-specific agonist salmeterol rescued wild-type animals from a lethal LPS challenge, which was reversed by neutralizing anti-IL-10 antibody. These observations suggest that ADRB2 signaling is critical for controlling inflammation through the rapid induction of IL-10. Transcriptome analysis revealed that the NR4A nuclear orphan family members were induced by NE. 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. Additionally, mice that deficient in NR4A1 are susceptible in LPS endotoxemia model. These results suggest a novel pathway for control of inflammation via neuroendocrine cues. Understanding this pathway will provide new insights into how the nervous and immune systems communicate through ADRB2 signaling.