Deletion of tumour necrosis factor α receptor 1 elicits an increased TH17 immune response in the chronically inflamed liver.

Tumour necrosis factor α receptor 1 (TNFR1) activation is known to induce cell death, inflammation, and fibrosis but also hepatocyte survival and regeneration. The multidrug resistance protein 2 knockout (Mdr2) mice are a model for chronic hepatitis and inflammation-associated hepatocellular carcinoma (HCC) development. This study analysed how the absence of TNFR1 mediated signalling shapes cytokine and chemokine production, immune cell recruitment and ultimately influences liver injury and fibrotic tissue remodelling in the Mdr2 mouse model. We show that Tnfr1/Mdr2 mice displayed increased plasma levels of ALT, ALP, and bilirubin as well as a significantly higher collagen content, and markers of fibrosis than Mdr2 mice. The expression profile of inflammatory cytokines (Il1b, Il23, Tgfb1, Il17a), chemokines (Ccl2, Cxcl1, Cx3cl1) and chemokine receptors (Ccr6, Cxcr6, Cx3cr1) in livers of Tnfr1/Mdr2 mice indicated TH17 cell infiltration. Flow cytometric analysis confirmed that the aggravated tissue injury in Tnfr1/Mdr2 mice strongly correlated with increased hepatic recruitment of TH17 cells and enhanced IL-17 production in the injured liver. Moreover, we observed increased hepatic activation of RIPK3 in Tnfr1/Mdr2 mice, which was not related to necroptotic cell death. Rather, frequencies of infiltrating CX3CR1 monocytes increased over time in livers of Tnfr1/Mdr2 mice, which expressed significantly higher levels of Ripk3 than those of Mdr2 mice. Overall, we conclude that the absence of TNFR1-mediated signalling did not improve the pathological phenotype of Mdr2 mice. It instead caused enhanced infiltration of TH17 cells and CX3CR1 monocytes into the injured tissue, which was accompanied by increased RIPK3 activation and IL-17 production.