Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury

Significance Statement The detailed role of neural activity in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. This study shows that activation of β 2-adrenergic receptor (Adrb2) signaling in macrophages induces the expression of T cell Ig and mucin domain 3 ( Tim3 ), which contributes to anti-inflammatory phenotypic alterations. Experiments using conditional knockout mice reveal that macrophage Adrb2 signaling directly mitigates LPS-induced systemic inflammation and renal ischemia-reperfusion injury (IRI). The adoptive transfer of Adrb2 signal–activated macrophages also protects against renal IRI, in association with the accumulation of Tim3 -expressing macrophages in the renal tissue. These results indicate that macrophage Adrb2 signaling plays critical roles in the severity of AKI. Background The sympathetic nervous system regulates immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. This study focused on identifying the functions of sympathetic signaling in macrophages in LPS-induced sepsis and renal ischemia-reperfusion injury (IRI). Methods We performed RNA sequencing of mouse macrophage cell lines to identify the critical gene that mediates the anti-inflammatory effect of β 2-adrenergic receptor (Adrb2) signaling. We also examined the effects of salbutamol (a selective Adrb2 agonist) in LPS-induced systemic inflammation and renal IRI. Macrophage-specific Adrb2 conditional knockout (cKO) mice and the adoptive transfer of salbutamol-treated macrophages were used to assess the involvement of macrophage Adrb2 signaling. Results In vitro , activation of Adrb2 signaling in macrophages induced the expression of T cell Ig and mucin domain 3 ( Tim3 ), which contributes to anti-inflammatory phenotypic alterations. In vivo , salbutamol administration blocked LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific Adrb2 cKO mice. The adoptive transfer of salbutamol-treated macrophages also protected against renal IRI. Single-cell RNA sequencing revealed that this protection was associated with the accumulation of Tim3 -expressing macrophages in the renal tissue. Conclusions The activation of Adrb2 signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of Tim3 expression, which blocks LPS-induced systemic inflammation and protects against renal IRI.