Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation
Hirofumi Hirao, … , Fady M. Kaldas, Jerzy W. Kupiec-Weglinski
Hirofumi Hirao, … , Fady M. Kaldas, Jerzy W. Kupiec-Weglinski
Published February 1, 2023
Citation Information: J Clin Invest. 2023;133(3):e162940. https://doi.org/10.1172/JCI162940.
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Research Article

Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation

Abstract

Neutrophils, the largest innate immune cell population in humans, are the primary proinflammatory sentinel in the ischemia-reperfusion injury (IRI) mechanism in orthotopic liver transplantation (OLT). Carcinoembryonic antigen–related cell adhesion molecule 1 (CEACAM1, CC1, or CD66a) is essential in neutrophil activation and serves as a checkpoint regulator of innate immune-driven IRI cascade in OLT. Although CC1 alternative splicing generates two functionally distinct short and long cytoplasmic isoforms, their role in neutrophil activation remains unknown. Here, we undertook molecular and functional studies to interrogate the significance of neutrophil CC1 signaling in mouse and human OLT recipients. In the experimental arm, we employed a mouse OLT model to document that ablation of recipient-derived neutrophil CC1-long (CC1-L) isotype aggravated hepatic IRI by promoting neutrophil extracellular traps (NETs). Notably, by regulating the S1P–S1PR2/S1PR3 axis, neutrophil CC1-L determined susceptibility to NET formation via autophagy signaling. In the clinical arm, liver grafts from 55 transplant patients selectively enriched for neutrophil CC1-L showed relative resistance to ischemia-reperfusion (IR) stress/tissue damage, improved hepatocellular function, and clinical outcomes. In conclusion, despite neutrophils being considered a principal villain in peritransplant tissue injury, their CC1-L isoform may serve as a regulator of IR stress resistance/NETosis in human and mouse OLT recipients.

Authors

Hirofumi Hirao, Hidenobu Kojima, Kenneth J. Dery, Kojiro Nakamura, Kentaro Kadono, Yuan Zhai, Douglas G. Farmer, Fady M. Kaldas, Jerzy W. Kupiec-Weglinski

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Figure 1

Recipient-derived CC1-L–expressing neutrophils infiltrate mouse OLT.

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Recipient-derived CC1-L–expressing neutrophils infiltrate mouse OLT. (A)...
(A) Mouse donor livers, stored in UW solution (4°C/18 hours), were transplanted into groups of WT and CC1-KO recipients, and OLT samples were collected at 6 hours after reperfusion. WB of CC1-S and CC1-L in naive and posttransplant livers (WT→WT, CC1-KO→WT, WT→CC1-KO). (B) WB of CC1-S and CC1-L in cultured murine cells (LSECs, BMDMs, hepatocytes, and neutrophils). (C) Representative (n = 3) IF images of CC1 (green), Ly6G (purple), and DAPI (blue) in OLT (WT→WT, CC1-KO→WT, WT→CC1-KO). Original magnification, ×200. (D) Representative (n = 3) IF images of CC1 (green), CD68 (red), and DAPI (blue) in OLT (WT→WT). Original magnification, ×200 (top rows); ×1200 (bottom 3 rows).