Hasegawa Sho, Inoue Tsuyoshi, Nakamura Yasuna, Fukaya Daichi, Uni Rie, Wu Chia-Hsien, Fujii Rie, Peerapanyasut Wachirasek, Taguchi Akashi, Kohro Takahide, Yamada Shintaro, Katagiri Mikako, Ko Toshiyuki, Nomura Seitaro, Nakanishi Ozeki Atsuko, Susaki Etsuo A, Ueda Hiroki R, Akimitsu Nobuyoshi, Wada Youichiro, Komuro Issei, Nangaku Masaomi, Inagi Reiko
Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
J Am Soc Nephrol. 2021 Jul;32(7):1599-1615. doi: 10.1681/ASN.2020121723. Epub 2021 Apr 19.
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).
We performed RNA sequencing of mouse macrophage cell lines to identify the critical gene that mediates the anti-inflammatory effect of 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 conditional knockout (cKO) mice and the adoptive transfer of salbutamol-treated macrophages were used to assess the involvement of macrophage Adrb2 signaling.
, activation of Adrb2 signaling in macrophages induced the expression of T cell Ig and mucin domain 3 (), which contributes to anti-inflammatory phenotypic alterations. , salbutamol administration blocked LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific 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 -expressing macrophages in the renal tissue.
The activation of Adrb2 signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of expression, which blocks LPS-induced systemic inflammation and protects against renal IRI.
交感神经系统调节免疫细胞动力学。然而，交感神经信号在炎症性疾病中的具体作用仍不清楚，因为它因疾病情况和相关细胞类型而异。本研究聚焦于确定交感神经信号在脂多糖诱导的脓毒症和肾缺血再灌注损伤（IRI）中巨噬细胞的功能。
我们对小鼠巨噬细胞系进行RNA测序，以鉴定介导β2 -肾上腺素能受体（Adrb2）信号抗炎作用的关键基因。我们还研究了沙丁胺醇（一种选择性Adrb2激动剂）在脂多糖诱导的全身炎症和肾IRI中的作用。利用巨噬细胞特异性条件性敲除（cKO）小鼠和经沙丁胺醇处理的巨噬细胞的过继转移来评估巨噬细胞Adrb2信号的参与情况。
巨噬细胞中Adrb2信号的激活诱导了T细胞免疫球蛋白和粘蛋白结构域3（Tim-3）的表达，这有助于抗炎表型改变。其次，给予沙丁胺醇可阻断脂多糖诱导的全身炎症并预防肾IRI；在巨噬细胞特异性cKO小鼠中这种保护作用减弱。经沙丁胺醇处理的巨噬细胞的过继转移也能预防肾IRI。单细胞RNA测序显示这种保护作用与肾组织中表达Tim-3的巨噬细胞的积累有关。
巨噬细胞中Adrb2信号的激活部分通过诱导Tim-3表达诱导抗炎表型改变，从而阻断脂多糖诱导的全身炎症并预防肾IRI。
