UC-1770

Sepsis-related acute liver injury involves complex immune dysfunctions. Epoxyeicosatrienoic acids (EETs), bioactive molecules derived from arachidonic acid (AA) via cytochrome P450 (CYP450) and rapidly hydrolyzed by soluble epoxide hydrolase (sEH), possess anti-inflammatory properties. Nevertheless, the impact of the sEH inhibitor TPPU on sepsis-related acute liver injury remains uncertain.

This study utilized comprehensive single-cell analysis to investigate the immunoregulatory mechanism of TPPU in alleviating sepsis-related acute liver injury.

Hepatic bulk RNA sequencing and proteomics analyses were employed to investigate the mechanisms underlying sepsis-related acute liver injury induced by cecal ligation and puncture in mice. Cytometry by time-of-flight and single-cell RNA sequencing were conducted to thoroughly examine the immunoregulatory role of TPPU at single-cell resolution.

Downregulation of AA metabolism and the CYP450 pathway was observed during sepsis-related acute liver injury, and TPPU treatment reduced inflammatory cytokine production and mitigated sepsis-related hepatic inflammatory injury. Comprehensive single-cell analysis revealed that TPPU promotes the expansion of anti-inflammatory CD206⁺CD73⁺ M2-like macrophages and PDL1^-CD39^-CCR2⁺ neutrophils, reprogramming liver neutrophils to an anti-inflammatory CAMP⁺NGP⁺CD177⁺ phenotype. Additionally, TPPU inhibits the CCL6-CCR1 signaling mediated by M2-like macrophages and CAMP⁺NGP⁺CD177⁺ neutrophils, altering intercellular communication within the septic liver immune microenvironment.

This study demonstrated TPPU's protective efficacy against sepsis-related acute liver injury, underscoring its vital role in modulating liver macrophages and neutrophils and enhancing prospects for personalized immunomodulatory therapy.

Abdominal aortic aneurysm (AAA), albeit usually asymptomatic, is highly lethal if ruptured. The 28-member transient receptor potential (TRP) ion channel superfamily, most of which are present in the aortic cells, is understudied in AAA. We aim to identify single TRP channel that could represent a novel therapeutic target, and dissect dysfunctional ionic signaling that drives AAA.

AAA was developed in mice by perfusing porcine pancreatic elastase into the infrarenal abdominal aorta. AAA was assessed by measurement of external diameter with a digital caliper, or internal diameter with ultrasonography. Aortic pathohistology was evaluated via histological and immunohistochemical staining. The TRP channel family was analyzed in the GSE17901 dataset. TRPC6, TRPC1/4/5 and TRPC3 channels were blocked in aneurysmal mice by BI749327, Pico145 and Pyr3, respectively. Endothelial cell-selective Trpv4 knockout mice were generated and leveraged for AAA analysis. TRPV4 channel was activated indirectly by TPPU or directly opened by GSK1016790A.

RNA-seq data mining revealed altered expression profiles of Trpc3/Trpc6, Trpv4. Pharmacological block of TRPC6, TRPC1/4/5 or TRPC3 did not influence AAA, whereas selective deletion of endothelial TRPV4 protected against AAA in endothelial cell-selective Trpv4 knockout mice. Indirect activation of TRPV4 by TPPU exacerbated AAA, but TRPV4-mediated nitric oxide signaling contributed minimally to AAA. TRPV4 activation promoted endothelial cell apoptosis in a Ca²⁺-dependent manner, a relevant mechanism underlying AAA.

Our data underscore the pathogenic importance of Ca²⁺ perturbation in AAA and illuminate that endothelial TRPV4 cation channel could be harnessed for AAA treatment.