Gut-Liver Crosstalk: A Novel Cd226-Cd112 Inhibitor Prevents Gut-Primed Netosis and Attenuates Acute Liver Injury in Sepsis

BACKGROUND: We recently identified a novel interaction between intestinal intraepithelial lymphocytes (IELs) and neutrophils via CD226 and CD112. This interaction induces neutrophil extracellular trap (NET) formation and promotes inflammatory gut-liver crosstalk in sepsis. By mapping the binding site between CD112 and CD226, DPX2 was created to inhibit IEL-induced NET formation. We hypothesize that DPX2 treatment inhibits IEL-mediated NETosis and the subsequent pathologic gut-liver crosstalk. METHODS: Adult C57BL/6 mice were subjected to sepsis by cecal ligation and puncture (CLP). The treatment group received a 1 μg/g BW i.p. injection of DPX2, while the control group received PBS as vehicle. Liver tissue was evaluated for pro-inflammatory markers, myeloperoxidase (MPO) activity, and TUNEL staining. Serum was analyzed for liver enzyme and cytokine levels. A 7-day survival study was also conducted. RESULTS: NETs in the portal vein blood and MPO in the liver were increased in septic mice but were significantly reduced by DPX2. Liver tissue levels of inflammatory markers were increased in vehicle-treated septic mice, whereas these parameters were significantly decreased in the DPX2 group. TUNEL staining as well as transaminase levels revealed significant elevations in the vehicle group with significant reduction in hepatocyte injury/death with DPX2. Systemic inflammatory markers were significantly increased in the vehicle group but were significantly decreased in the DPX2 group. Lastly, there was a significant improvement in survival in the DPX2 group compared to the vehicle group. CONCLUSIONS: Treatment with DPX2 reduces NETosis, acute liver injury, and systemic inflammatory response, leading to improved survival in sepsis.