The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma

Juan Wu, Jiaqi Li, Rosalba Salcedo, Nahid F. Mivechi, Giorgio Trinchieri, Anatolij Horuzsko

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

Chronic inflammation drives liver cancer pathogenesis, invasion, andmetastasis. Liver Kupffer cells 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 proinflammatory myeloid cell surface receptor TREM-1 expressed by Kupffer cells 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 Kupffer cell activation by downregulating transcription and protein expression of interleukin (IL)-6, IL-1β, TNF, CCL2, and CXCL10. In addition, Trem1 ablation diminished activation of the p38, extracellular regulated kinase 1/2, JNK,mitogen-activated protein kinase, and NF-κB signaling pathways in Kupffer cells, resulting in diminished liver injury after DEN exposure. Adoptive transfer of wild-type Kupffer cells 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 Kupffer cell activation in liver carcinogenesis, deepening mechanistic insights into how chronic inflammation underpins the development and progression of liver cancer.

Original languageEnglish (US)
Pages (from-to)3977-3986
Number of pages10
JournalCancer Research
Volume72
Issue number16
DOIs
StatePublished - Aug 15 2012

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Kupffer Cells
Myeloid Cells
Hepatocellular Carcinoma
Liver Neoplasms
Diethylnitrosamine
Liver
Carcinogenesis
Inflammation
Proto-Oncogene Proteins c-akt
Adoptive Transfer
JNK Mitogen-Activated Protein Kinases
Wounds and Injuries
Cell Surface Receptors
Interleukin-1
Transcriptional Activation
Interleukin-6
Phosphotransferases
Down-Regulation
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. / Wu, Juan; Li, Jiaqi; Salcedo, Rosalba; Mivechi, Nahid F.; Trinchieri, Giorgio; Horuzsko, Anatolij.

In: Cancer Research, Vol. 72, No. 16, 15.08.2012, p. 3977-3986.

Research output: Contribution to journalArticle

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