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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.

Nucleotide-binding domain leucine-rich repeat containing receptors (NLRs) are cytosolic receptors that initiate immune responses to sterile and infectious insults to the host. Studies demonstrated that Nlrp3 is critical for the control of Candida albicans infections and in the generation of antifungal Th17 responses. In this article, we show that the NLR family member Nlrp10 also plays a unique role in the control of disseminated C. albicans infection in vivo. Nlrp10-deficient mice had increased susceptibility to disseminated candidiasis, as indicated by decreased survival and increased fungal burdens. In contrast to Nlrp3, Nlrp10 deficiency did not affect innate proinflammatory cytokine production from macrophages and dendritic cells challenged with C. albicans. However, Nlrp10-deficient mice displayed a profound defect in Candida-specific Th1 and Th17 responses. These results demonstrate a novel role for Nlrp10 in the generation of adaptive immune responses to fungal infection.

The NLRP3 inflammasome is activated in response to a variety of signals that are indicative of damage to the host including tissue damage, metabolic stress, and infection. Upon activation, the NLRP3 inflammasome serves as a platform for activation of the cysteine protease caspase-1, which leads to the processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Dysregulated NLRP3 inflammasome activation is associated with both heritable and acquired inflammatory diseases. Here, we review new insights into the mechanism of NLRP3 inflammasome activation and its role in disease pathogenesis.

Type 2 T helper (T(H)2) cells are critical for the development of allergic immune responses; however, the molecular mechanism controlling their effector function is still largely unclear. Here, we report that the transcription factor NFIL3/E4BP4 regulates cytokine production and effector function by T(H)2 cells. NFIL3 is highly expressed in T(H)2 cells but much less in T(H)1 cells. Production of interleukin (IL)-13 and IL-5 is significantly increased in Nfil3(-/-) T(H)2 cells and is decreased by expression of NFIL3 in wild-type T(H)2 cells. NFIL3 directly binds to and negatively regulates the Il13 gene. In contrast, IL-4 production is decreased in Nfil3(-/-) T(H)2 cells. Increased IL-13 and IL-5 together with decreased IL-4 production by antigen-stimulated splenocytes from the immunized Nfil3(-/-) mice was also observed. The ability of NFIL3 to alter T(H)2 cytokine production is a T-cell intrinsic effect. Taken together, these data indicate that NFIL3 is a key regulator of T(H)2 responses.