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Kidney Week

Abstract: FR-PO120

Cholinergic Signaling Increases Macrophage-Macrophage Interactions and Protects Sepsis-Induced AKI

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Nakamura, Yasuna, Nagasaki Daigaku Igakubu Daigakuin Ishiyakugaku Sogo Kenkyuka, Nagasaki, Nagasaki, Japan
  • Inoue, Tsuyoshi, Nagasaki Daigaku Igakubu Daigakuin Ishiyakugaku Sogo Kenkyuka, Nagasaki, Nagasaki, Japan
  • Inagi, Reiko, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
  • Nangaku, Masaomi, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
Background

Nicotinic acetylcholine receptor agonists have been shown to activate the cholinergic anti-inflammatory pathway (CAP) and improve systemic inflammation and acute kidney injury. This inflammatory reflex is known as a nervous system-mediated immune response. It is considered that the CAP activation is thought to be through α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages, but no one has been demonstrated it in vivo.

Methods

To confirm the importance of α7nAChR in macrophages in vivo, macrophage-specific α7nAChR knockout (KO) mice (LysM-Cre: Chrna7flox/flox mice) were generated and tested whether GTS-21 (α7nAChR specific agonists) ameliorates lipopolysaccharide (LPS)-induced kidney injury. We also performed single-cell RNA sequencing (sc-RNA seq) of the spleen to identify the cells or genes that receive cholinergic signals in the spleen under LPS administration comprehensively.

Results

Administration of GTS-21 resulted in a decrease in systemic TNF-α production and kidney Ngal elevations by LPS in littermate wild-type (WT) mice, whereas the decreases were not observed in KO mice. This result suggested that the cholinergic signaling is mediated by α7nAChR on macrophages even in vivo. In addition, sc-RNA seq identified that GTS-21 administration induces cell-cell interactions between macrophage-macrophages. In vitro transwell experiments using the macrophage cell line RAW 264 showed that GTS-21 increases macrophage-to-macrophage contacts. Furthermore, co-culture of macrophages suppressed TNF-α production induced by LPS as well as GTS-21 treatments. The anti-inflammatory and renal protective effects were canceled by splenectomy, suggesting that macrophage-macrophage cell interactions in the spleen are essential even in vivo.

Conclusion

Activation of cholinergic signaling via α7nAChR on macrophages increases macrophage-macrophage interactions in the spleen, resulting in anti-inflammatory and renoprotective effects in LPS-induced acute kidney injury.

Funding

  • Government Support – Non-U.S.