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

Sho Hasegawa; Tsuyoshi Inoue; Yasuna Nakamura; Daichi Fukaya; Rie Uni; Chia-Hsien Wu; Rie Fujii; Wachirasek Peerapanyasut; Akashi Taguchi; Takahide Kohro; Shintaro Yamada; Mikako Katagiri; Toshiyuki Ko; Seitaro Nomura; Atsuko Nakanishi Ozeki; Etsuo A Susaki; Hiroki R Ueda; Nobuyoshi Akimitsu; Youichiro Wada; Issei Komuro; Masaomi Nangaku; Reiko Inagi

doi:10.1681/ASN.2020121723

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

J Am Soc Nephrol. 2021 Jul;32(7):1599-1615. doi: 10.1681/ASN.2020121723. Epub 2021 Apr 19.

Authors

Sho Hasegawa^{1

2}, Tsuyoshi Inoue^{2

3}, Yasuna Nakamura^{1

3}, Daichi Fukaya^{2

4}, Rie Uni^{1

2}, Chia-Hsien Wu^{1

3}, Rie Fujii^{1

2}, Wachirasek Peerapanyasut^{2

5}, Akashi Taguchi⁶, Takahide Kohro⁷, Shintaro Yamada^{8

9}, Mikako Katagiri⁸, Toshiyuki Ko^{8

9}, Seitaro Nomura^{8

9}, Atsuko Nakanishi Ozeki⁶, Etsuo A Susaki^{10

11}, Hiroki R Ueda^{10

11}, Nobuyoshi Akimitsu⁶, Youichiro Wada⁶, Issei Komuro⁸, Masaomi Nangaku¹, Reiko Inagi²

Affiliations

¹ Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
² Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
³ Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
⁴ Department of Nephrology, Saitama Medical University, Saitama, Japan.
⁵ Mahidol University, Nakhonsawan Campus, Nakhonsawan, Thailand.
⁶ Isotope Science Center, University of Tokyo, Tokyo, Japan.
⁷ Department of Clinical Informatics/Cardiology, Jichi Medical University, Tochigi, Japan.
⁸ Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
⁹ Genome Science Division, Research Center for Advanced Science and Technologies, University of Tokyo, Tokyo, Japan.
¹⁰ Department of Systems Pharmacology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
¹¹ Laboratory for Synthetic Biology, RIKEN Center for Biosystems Dynamics Research, Suita, Japan.

Abstract

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 β2-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.

Keywords: acute renal failure; cell biology and structure; cell signaling; cell transfer; clinical immunology; cytokines; immunology; ischemia-reperfusion; kidney; macrophages.