LAUSR

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.