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Kidney Week

Abstract: PO0150

Sympathetic Signaling in Macrophages Mitigates Systemic Inflammatory Response and Renal Ischemia-Reperfusion Injury

Session Information

  • AKI Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Hasegawa, Sho, The University of Tokyo, Tokyo, Japan
  • Inoue, Tsuyoshi, Nagasaki University, Nagasaki, Japan
  • Nangaku, Masaomi, The University of Tokyo, Tokyo, Japan
  • Inagi, Reiko, The University of Tokyo, Tokyo, Japan

The sympathetic nervous system is known to control immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear. Here, we focused on sympathetic signaling in macrophages and aimed to determine whether its activation attenuates lipopolysaccharide (LPS)-induced sepsis and renal ischemia/reperfusion injury (rIRI).


<In vitro> Three types of macrophages (RAW 264.7 cells [murine macrophage cell line], murine peritoneal cells, and differentiated U937 cells [human monocyte cell line]) were used to determine the effects of sympathetic signaling, especially β2 adrenergic receptor (ADRB2) signaling, on LPS-induced proinflammatory cytokine (TNF-α) production.
<In vivo> We examined the effects of salbutamol (β2 selective agonist) on LPS-induced sepsis and rIRI models. Macrophage-specific ADRB2 conditional knockout (ADRB2 cKO) mice were used to elucidate the contribution of ADRB2 signaling in macrophages.


<In vitro> Norepinephrine, a main sympathetic neurotransmitter, reduced LPS-induced TNF-α production in the three types of macrophages. This anti-inflammatory effect was also induced by salbutamol and reversed by butoxamine (β2 selective antagonist) in a dose-dependent manner, indicating the importance of ADRB2 in this process. Furthermore, T-cell immunoglobulin and mucin-3 (TIM-3) expression was upregulated in macrophages by ADRB2 signaling and partially mediated the anti-inflammatory phenotypic alteration.
<In vivo> Salbutamol administration immediately before LPS treatment significantly reduced plasma TNF-α levels in mice, which was mitigated in macrophage-specific ADRB2 cKO mice. Salbutamol administration 24 h before rIRI also attenuated acute kidney injury, which was relieved in macrophage-specific ADRB2 cKO mice. The protection against rIRI was abolished in the mice in which splenectomy was performed 10 days before salbutamol administration, which suggests the contribution of splenic macrophages to the protective effects. In fact, adoptive transfer of salbutamol-treated splenic macrophages conferred protection to the recipient mice subjected to rIRI.


Sympathetic signaling via ADRB2 in macrophages attenuates systemic inflammatory response and rIRI. Phenotypic alterations in splenic macrophages might play critical roles in the protection against rIRI.


  • Government Support - Non-U.S.