# A novel CD112-derived peptide targeting gut-primed neutrophils to attenuate deadly hepatic injury

## TL;DR

A new peptide called DPX2 can reduce liver damage caused by gut inflammation by blocking harmful interactions between neutrophils and gut lymphocytes.

## Contribution

A novel CD112-derived peptide, DPX2, is developed to inhibit neutrophil-IEL interactions and mitigate hepatic injury.

## Key findings

- Neutrophils in contact with IELs in gut I/R mice show increased NET formation and migration to the liver.
- DPX2 administration reduces NET-forming neutrophils and liver inflammation markers in gut I/R mice.
- DPX2 significantly attenuates liver injury indicators like AST, ALT, and tissue damage scores.

## Abstract

Gut-liver crosstalk exacerbates hepatic injury in gut ischemia/reperfusion (I/R), but its mechanism and therapeutic intervention remain elusive. Given the important roles of neutrophils and gut-resident intraepithelial lymphocytes (IELs) during acute inflammation, we hypothesized that the interaction between these two cell types worsens liver injury during gut I/R.

Gut I/R was induced in mice by occluding superior mesenteric artery (SMA) for 60 min, followed by 4 h resuscitation. Blood, intestine and liver tissues were collected for various analysis. Neutrophil extracellular traps (NETs) were determined by microscopy. Gut I/R mice were injected (i.p.) with DPX2 (1 µg/g BW) at the time of reperfusion. After 4 h, blood and liver tissues were collected for various analysis.

We discovered that neutrophils in contact with IELs in gut I/R mice had increased ability to form NETs. As such, NETs+ neutrophils were increased in the portal vein blood of gut I/R mice compared to sham mice and the systemic blood, accompanied by increased NETs in the liver, indicating the migration of the activated neutrophils from the gut to the liver. Adoptive transfer of IEL-primed neutrophils into gut I/R mice exacerbated liver inflammation as indicated by increased liver tissue levels of inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), keratinocyte-derived chemokine (KC), and C-X-C motif chemokine ligand 2 (CXCL2). The interaction of neutrophils and IELs is known to be mediated via neutrophil CD112. Increased numbers of CD112+ neutrophils were observed in the gut epithelium after gut I/R. We have discovered a CD112-derived peptide, named DPX2, which inhibits the interaction between CD112 on neutrophils and its proinflammatory ligand CD226 on IELs. In vitro, DPX2 attenuated IEL-induced NETosis under inflammatory conditions. In vivo, the administration of DPX2 significantly decreased NET-forming neutrophils in the portal vein of gut I/R mice. In parallel to NETs inhibition, DPX2 administration significantly mitigated the gene expression of iNOS, IL-6, IL-1β, KC, and CXCL2 in the liver. Furthermore, the administration of DPX2 significantly attenuated liver injury as indicated by decreased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), tissue injury score, and liver cell death.

Neutrophil-gut IEL interaction mediates proinflammatory gut-liver crosstalk and the novel CD112-derived peptide DPX2 targeting this interaction has the potential to mitigate hepatic injury.

The online version contains supplementary material available at 10.1186/s10020-026-01426-3.