Sour neuronal signalling attenuates macrophage-mediated liver injury

Abstract

Background & aims: 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 ischaemia-reperfusion injury (IRI) in mice. Next, we analysed the altered gene expression of neurons during liver IRI by single-cell sequencing. In addition, we explored the effect 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 neurone-derived TAFA2 recruits CCR2⁺ macrophages to the liver and triggers liver injury, which is at least partly reduced by nerve signalling in response to sour stimuli, i.e. consumption of acidic substances. Our findings provide new insights into the brain-liver axis and potential therapeutic approaches for liver injury.

Impact and implications: In this study, we demonstrated that sour stimuli, which are related to consumption of acidic foods, are at least partly responsible for reducing human and mouse liver ischaemia-reperfusion injury (IRI), and we confirmed the important role of the brain-liver axis in liver IRI. In this study, we found that the brain-liver axis increases liver IRI through the secretion of TAFA2 protein. TAFA2 mediated liver IRI through the recruitment and activation of macrophages via the receptor CCR2. Additionally, TAFA2 was shown to induce a proinflammatory transcriptional profile in macrophages. Our findings provide new insights into the brain-liver axis and uncover a potential therapeutic strategy to reduce IRI.

Clinical trial number: This clinical trial was registered with the Chinese Clinical Trial Registry (ChiCTR2400088096).

Keywords: CCR2; Fam19a2; Liver ischemia-reperfusion injury; Macrophages; Neuroimmunity; Sour stimulation; TAFA2.