Salmeterol, agonist of β2-aderenergic receptor, prevents systemic inflammation via inhibiting NLRP3 inflammasome.

β2-Aderenergic receptor (β2AR) agonist, Salmeterol exhibits anti-inflammatory activities. However, the inhibitory effects of Salmeterol on inflammasome activation are elusive and the underlying mechanisms need to be explored. In this study, we established inflammatory model in primary bone marrow-derived macrophages (BMDM) from C57BL/6J mice and β-arrestin2 knockout (β-arrestin2) mice in vitro. In vivo study by LPS intraperitoneally (i.p.) in C57BL/6J mice was carried out to ascertain its roles in systemic inflammation. We found that Salmeterol (10 M-10 M) prevented the cleavage of caspase-1 and the activation of NLRP3 inflammasome, reduced the release of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in vitro. Blockade of adenosine3',5'cyclic monophosphate (cAMP)/protein kinase A (PKA) pathway with cAMP or PKA inhibitors inhibited anti-inflammatory effects of Salmeterol only at 10 M. Depletion of β-arrestin2 compromised the inhibitory effects of Salmeterol at both 10 M and 10 M. Salmeterol increased the interaction of β-arrestin2 and NLRP3. In vivo study showed that Salmeterol decreased the serum concentrations of pro-inflammatory cytokines IL-1β and TNF-α, blocked cleavage of caspase-1 and release of IL-1β in BMDM. These findings imply that Salmeterol at low concentrations (10 M-10 M) shows anti-inflammatory effect via inhibiting NLRP3 inflammasome. The underlying mechanisms is dosage-dependent: Salmeterol at 10 M shows anti-inflammatory effects through β-arrestin2 pathway, and 10 M Salmeterol inhibits inflammation via both classical G-protein coupled receptor (GPCR)/cAMP pathway and β-arrestin2 pathway. These results provide new ideas for the future treatment of systemic inflammation and other inflammatory diseases.