Sho Hasegawa1,2, Tsuyoshi Inoue3,4, Yasuna Nakamura1,4, Daichi Fukaya2,5, Rie Uni6,2, Chia-Hsien Wu1,4, Rie Fujii1,2, Wachirasek Peerapanyasut2,7, Akashi Taguchi8, Takahide Kohro9, Shintaro Yamada10,11, Mikako Katagiri10, Toshiyuki Ko10,11, Seitaro Nomura10,11, Atsuko Nakanishi Ozeki8, Etsuo A Susaki12,13, Hiroki R Ueda12,13, Nobuyoshi Akimitsu8, Youichiro Wada8, Issei Komuro10, Masaomi Nangaku1, Reiko Inagi2. 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. Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan ts-inoue@nagasaki-u.ac.jp. 4. Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 5. Department of Nephrology, Saitama Medical University, Saitama, Japan. 6. Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan ts-inoue@nagasaki-u.ac.jp. 7. Mahidol University, Nakhonsawan Campus, Nakhonsawan, Thailand. 8. Isotope Science Center, University of Tokyo, Tokyo, Japan. 9. Department of Clinical Informatics/Cardiology, Jichi Medical University, Tochigi, Japan. 10. Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan. 11. Genome Science Division, Research Center for Advanced Science and Technologies, University of Tokyo, Tokyo, Japan. 12. Department of Systems Pharmacology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan. 13. 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.
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.
Authors: Mauricio Rosas-Ballina; Peder S Olofsson; Mahendar Ochani; Sergio I Valdés-Ferrer; Yaakov A Levine; Colin Reardon; Michael W Tusche; Valentin A Pavlov; Ulf Andersson; Sangeeta Chavan; Tak W Mak; Kevin J Tracey Journal: Science Date: 2011-09-15 Impact factor: 47.728
Authors: Tsuyoshi Inoue; Chikara Abe; Sun-Sang J Sung; Stefan Moscalu; Jakub Jankowski; Liping Huang; Hong Ye; Diane L Rosin; Patrice G Guyenet; Mark D Okusa Journal: J Clin Invest Date: 2016-04-18 Impact factor: 14.808
Authors: Taka-Aki Nakada; James A Russell; John H Boyd; Rosalia Aguirre-Hernandez; Katherine R Thain; Simone A Thair; Emiri Nakada; Melissa McConechy; Keith R Walley Journal: Am J Respir Crit Care Med Date: 2009-10-22 Impact factor: 21.405