The Proinflammatory Myeloid Cell Receptor TREM-1 Controls Kupffer Cell Activation and Development of Hepatocellular Carcinoma

Abstract

Chronic inflammation drives liver cancer pathogenesis, invasion and metastasis. Liver Kupffer cells (KC) have crucial roles in mediating the inflammatory processes that promote liver cancer but the mechanistic basis for their contributions are not fully understood. Here we show that expression of the pro-inflammatory myeloid cell surface receptor TREM-1 expressed by KC is a crucial factor in the development and progression of liver cancer. Deletion of the murine homolog Trem1 in mice attenuated hepatocellular carcinogenesis triggered by diethylnitrosamine (DEN). Trem1 deficiency attenuated KC activation by downregulating transcription and protein expression of IL-6, IL-1β, TNF, CCL2 and CXCL10. In addition, Trem1 ablation diminished activation of the p38, ERK1/2, JNK, MAPK and NF-κB signaling pathways in KC, resulting in diminished liver injury after DEN exposure. Adoptive transfer of wild-type KC to Trem1-deficient mice complemented these defects and reversed unresponsiveness to DEN-induced liver injury and malignant development. Together, our findings offer causal evidence that TREM-1 is a pivotal determinant of KC activation in liver carcinogenesis, deepening mechanistic insights into how chronic inflammation underpins the development and progression of liver cancer.

GPR84 and TREM-1 Signaling Contribute to the Pathogenesis of Reflux Esophagitis

“…The simultaneous downregulation of the gene expression of TREM-1 and TREM-3 and the reversal of the upregulation and downregulation of SPIB, FOXO4 and FOXO6 after treatment with STW5 and omeprazole support a role of these transcription factors in inflammatory signaling. Recently, mice deficient in TREM-1 were generated, resulting in attenuated diethylnitrosamine-induced hepatocellular carcinoma (31), and TREM-1 blockade was shown to improve the clinical course of a murine model of IBD (25). Taken together, these data support a central role of TREM-1 in gastrointestinal (GI) inflammation and cancer progression.…”

GdCl3 suppresses the malignant potential of hepatocellular carcinoma by inhibiting the expression of CD206 in tumor-associated macrophages

“…Horseradish peroxidase (HRP)-conjugated anti-rabbit secondary antibody and DAB reagent were obtained from Dako (Glostrup, Denmark). Lipopolysaccharide (LPS) from Escherichia coli 011:B4, GdCl 3 [gadolinium (III) chloride hexahydrate], and N-nitrosodiethylamine (DEN) were obtained from Sigma-Aldrich (St. Louis, MO, uSA). IL-4 (recombinant murine IL-4) was purchased from PeproTech (Rocky Hill, NJ, uSA).…”

“…HCC normally develops from chronic inflammation in which tumor-associated macrophages (TAMs), a paradigm for polarized M2 mononuclear phagocytes, play a critical role in inflammatory processes and promote disease progression (2)(3)(4). TAMs mediate tumor cell migration, invasion, proliferation and trigger the malignant potential of HCC by activating certain intracellular signaling pathways (5)(6)(7).…”

“…However, apart from certain drugs used in the clinic such as trabectedin, (10) most of the reagents are still under pre-clinical investigation. Gadolinium chloride (GdCl 3 ) is an injectable MRI contrast agent used in the clinic (11)(12)(13)) that is also widely used for macrophage blockage in animal experiments. This drug may have applications for TAM blockage in human cancers.…”

Mechanism of Kupffer cells in hepatitis infected by hepatitis B and C virus

“…18,31 So the cytokines such as IL-6 and TNF, which are secreted by KCs, remain to be at a high level and cause the excessive inflammation as well as the compensative proliferation of residual hepatocytes to maintain the form and function of the liver. The cyclic process of hepatocytes death and multiplication could increase the chance of DNA spontaneity mutations and damages,which is considered as the highly risk factors of hepatocellular carcinoma.…”