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NOD-like receptor C4 Inflammasome Regulates the Growth of Colon Cancer Liver Metastasis in NAFLD.

  • Author(s): Ohashi, Koichiro
  • Wang, Zhijun
  • Yang, Yoon Mee
  • Billet, Sandrine
  • Tu, Wei
  • Pimienta, Michael
  • Cassel, Suzanne L
  • Pandol, Stephen J
  • Lu, Shelly C
  • Sutterwala, Fayyaz S
  • Bhowmick, Neil
  • Seki, Ekihiro
  • et al.

Published Web Location

Nonalcoholic fatty liver disease (NAFLD) enhances the growth and recurrence of colorectal cancer (CRC) liver metastasis. With the rising prevalence of NAFLD, a better understanding of the molecular mechanism underlying NAFLD-associated liver metastasis is crucial. Tumor-associated macrophages (TAMs) constitute a large portion of the tumor microenvironment that promotes tumor growth. NOD-like receptor C4 (NLRC4), a component of an inflammasome complex, plays a role in macrophage activation and interleukin (IL)-1β processing. We aimed to investigate whether NLRC4-mediated TAM polarization contributes to metastatic liver tumor growth in NAFLD. Wild-type and NLRC4-/- mice were fed low-fat or high-fat diet for 6 weeks followed by splenic injection of mouse CRC MC38 cells. The tumors were analyzed 2 weeks after CRC cell injection. High-fat diet-induced NAFLD significantly increased the number and size of CRC liver metastasis. TAMs and CD206-expressing M2 macrophages accumulated markedly in tumors in the presence of NAFLD. NAFLD up-regulated the expression of IL-1β, NLRC4, and M2 markers in tumors. In NAFLD, but not normal livers, deletion of NLRC4 decreased liver tumor growth accompanied by decreased M2 TAMs and IL-1β expression in tumors. Wild-type mice showed increased vascularity and vascular endothelial growth factor (VEGF) expression in tumors with NAFLD, but these were reduced in NLRC4-/- mice. When IL-1 signaling was blocked by recombinant IL-1 receptor antagonist, liver tumor formation and M2-type macrophages were reduced, suggesting that IL-1 signaling contributes to M2 polarization and tumor growth in NAFLD. Finally, we found that TAMs, but not liver macrophages, produced more IL-1β and VEGF following palmitate challenge. Conclusion: In NAFLD, NLRC4 contributes to M2 polarization, IL-1β, and VEGF production in TAMs, which promote metastatic liver tumor growth.

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