Sour neuronal signalling attenuates macrophage mediated liver injury.

Background: Liver injury, a common pathophysiological basis of various liver diseases, is associated with inflammation. Hepatic nerves regulate inflammation. However, the specific signals that trigger inflammation and methods to treat inflammation by targeting nerves remain unknown.

Methods: First, we constructed an animal model to detect the effect of sour stimuli on liver ischemia and reperfusion injury (IRI) in mice. Next, we analyzed the altered gene expression of neurons during liver IRI by single-cell sequencing. In additional, we explored the mechanism of sour stimuli on liver IRI in mice. Finally, we designed clinical trials to explore the effect of sour stimuli on liver IRI during hepatectomy.

Results: In this study, single-cell sequencing data from the liver and celiac ganglion showed that TAFA2 was induced in neurones during liver IRI, whereas sour stimuli decreased TAFA2 production and liver injury. In vivo studies showed that TAFA2 ablation and specific knockdown in neurones reduce liver injury. Using FLAG-tagged TAFA2, we found that TAFA2 interacted with Chemokine C-C-Motif Receptor 2 (CCR2) and promoted macrophage activation, consistent with RNA sequencing data showing that TAFA2 induced the expression of inflammatory genes in wild-type macrophages, but not in CCR2 knockout macrophages. Moreover, patients exposed to sour stimuli exhibited less severe liver IRI during hepatectomy.

Conclusions: Our results reveal a neuroimmune interaction in which neurones derived TAFA2 recruit CCR2+ macrophages to the liver and trigger liver injury, which is at least partly reduced by sour stimuli nerve signalling, which is related to acid with low pH. Our findings provide new insights into the brain-liver axis and therapeutic perspectives for liver injury.

Clinical Trial Number: This clinical trial was registered with the Chinese Clinical Trial Registry (ChiCTR2400088096) IMPACT AND IMPLICATIONS: ● This study clarified that sour stimuli, which is related to acid (low pH value), is at least partly responsible for reducing human and mouse liver ischemia and reperfusion injury through nerves, and confirmed the important role of brain-liver axis in liver ischemia and reperfusion injury.● This study found that brain-liver axis to increase liver ischemia-reperfusion injury through the secretion of TAFA2 protein, and proved that TAFA2 protein mediated liver ischemia-reperfusion injury through the recruitment and activation of macrophages.● This study found that CCR2 is the receptor for TAFA2 protein, and TAFA2 and CCL2 produce a different transcriptional profile by RNA sequencing.