Cell-autonomous hepatocyte-specific GP130 signalling is sufficient to trigger a robust innate immune response in mice.

BACKGROUND&AIM: IL-6 cytokine family members contribute to inflammatory and regenerative processes. Engagement of the signalling receptor subunit gp130 is common to almost all members of the family. In the liver, all major cell types respond to IL-6, making it difficult to delineate cell type-specific effects of IL-6 type cytokines. We therefore generated mouse models for liver cell type-specific analysis of IL-6 signalling.

METHODS: We produced mice with a Cre-inducible expression cassette encoding a designed pre-dimerized constitutive active gp130 variant. We bred these mice to different Cre-drivers to induce transgenic gp130 signalling in distinct liver cell types: hepatic stellate cells (HSCs), cholangiocytes (CCs)/liver progenitor cells (LPCs) or hepatocytes. We phenotyped these mice using multi-omics approaches, immunophenotyping and a bacterial infection model.

RESULTS: Hepatocyte-specific gp130 activation led to the up-regulation of innate immune system components, including acute-phase-proteins. Consequently, we observed peripheral mobilisation and recruitment of myeloid cells to the liver. Hepatic myeloid cells, including liver-resident Kupffer cells were instructed to adopt a bactericidal phenotype which ultimately conferred enhanced resistance to bacterial infection in these mice. We demonstrate that persistent hepatocyte-specific gp130 activation resulted in amyloid A amyloidosis in aged mice. In contrast, we did not observe overt effects of HSC or CC/LPC-specific transgenic gp130 signalling.

CONCLUSIONS: Hepatocyte-specific gp130 activation alone is sufficient to trigger a robust innate immune response in the absence of NFκB activation. We therefore conclude that gp130 engagement e.g. by IL-6 trans-signalling represents a safe-guard mechanism in innate immunity.