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

Abstract

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.

Cell Death in Liver Diseases: A Review

“…Whether this change in the microbiome is the result of less injury and inflammation or the driving force behind the liver damage is not clear. The deletion of TNF receptor in MDR2 KO mice (TNFR1 KO/MDR1 KO) aggravates hepatitis and fibrosis [ 245 ], and it is accompanied with increased RIPK3 but not pMLKL. RIPK3 expression correlated with the increase in CX3CR1 chemokine, and a significant increase in RIPK3 was seen in CD11b+CXCR1+ monocytes in the livers of TNFR1 KO/MDR1 KO mice, indicating a necroptosis-independent and inflammatory role for RIPK3 [ 245 ].…”

Imbalanced inflammatory response in subchronic arsenic‐induced liver injury and the protective effects of Ginkgo biloba extract in rats: Potential role of cytokines mediated cell–cell interactions

“…Recent years, increasing attention is being towards pathological immune responses in the pathogenesis of many different types of liver injuries, in which the role of Th17 and Treg cells that has been revealed gradually. Th17 cells, the recently identified pro‐inflammatory subset of CD4 + T helper cells has been proved important for the host against extracellular pathogenic substance, while, some literatures claimed that the overactivation of Th17 cells is pathogenic and closely related to the pathological processes of many liver disease 12,13 . Opposite to Th17 cells, another subset of CD4 + T cells that named regulatory T (Treg) cells are viewed as a critical immune‐suppressor in excessive inflammation responses, especially in autoimmune and inflammatory diseases 14 .…”

Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease

“…Furthermore, LI-MAIT cells produce IL-17A, which is known to activate HSCs and enhance the progression of liver fibrosis. [201][202][203] Böttcher et al showed that in AILDs, long-term stimulation of MAIT cells in the presence of IL-12 and IL-18, as well as bacterial antigens, fostered MAIT cell exhaustion due to chronic antigen exposure, although these cells expressed activation markers (CD38, HLA-DR and CD69). The exhausted phenotype was evident by the upregulation of PD-1, TIM-3, and CD39, with simultaneous increases in IFNγ expression.…”