Dectin3 protects against hepatocellular carcinoma by regulating glycolysis of macrophages.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the commonest cancer and is high in incidence. Besides, glycolysis has been proven to be a promoter in cancer progression. But the research related to glycolysis concentrates on tumor cells, and few are about macrophages. Dectin3 is a C-type Lectin receptor (CLR), expressed by myeloid lineage cells such as monocytes/macrophages, which can recognize pathogens and modulate immunity. We speculate that Dectin3 is involved in HCC by regulating the glycolysis in macrophages, which is meaningful. METHODS: Wild-type (WT) mice and Dectin3-/- mice were used to establish a mouse model of HCC and the progression of HCC was evaluated. Primary tumor associated macrophages (TAMs) were isolated from tumor tissues and the level of glycolysis was assessed. WT and Dectin3-/- tumor-bearing mice were treated with glycolysis inhibitors and the tumor progression was assessed. Culture supernatant derived from H22 cells was used to stimulate bone-marrow-derived macrophages (BMDMs). The level of glycolysis in BMDMs was subsequently detected. H22 cells and BMDMs were co-cultured and then the proliferation and apoptosis of H22 cells were evaluated. RESULTS: Compared with WT mice, tumor volume of Dectin3-/- mice increased, and the proportion of macrophages in tumor tissues increased, while the proportions of CD4+ and CD8+T cells decreased. Besides, the splenomegaly of Dectin3-/- mice was more serious. The level of glycolysis in macrophages of Dectin3-/- tumor-bearing mice was significantly up-regulated. After glycolysis inhibitor treatment, cancer progression of Dectin3-/- tumor-bearing mice slowed down, and the difference between WT mice and Dectin3-/- mice was significantly down-regulated. In addition, Dectin3 deficiency macrophages significantly promoted H22 cell proliferation and inhibited H22 cell apoptosis. CONCLUSION: Dectin3 can protect against HCC. Dectin3 contributes to the apoptosis of tumor cells and inhibits the proliferation of tumor cells by regulating the glycolysis of macrophages.

Card9 protects fungal peritonitis through regulating Malt1-mediated activation of autophagy in macrophage.

Fungal peritonitis is an inflammatory condition of the peritoneum which occurs secondary to peritoneal dialysis. Most cases of peritonitis are caused by microbial invasion into the peritoneal cavity, resulting in high morbidity and mortality. Unlike bacterial peritonitis, little is known on fungal peritonitis. Card9, an adapter protein, plays a critical role in anti-fungal immunity. In this study, by using zymosan-induced peritonitis and C. albicans-induced peritonitis mouse model, we demonstrated that fungal peritonitis was exacerbated in Card9-/- mice, compared with WT mice. Next, we found the autophagy activation of peritonealmacrophages was impaired in Card9-/- peritonitis mice. The autophagy agonist, MG132, ameliorated peritonitis in Card9-/- mice. The result of microarray analysis indicates Malt1 was significantly decreased in Card9-/- peritonitis mice. Furthermore, we demonstrated that Malt1 interacts with P62 and mediates the function of P62 to clear ubiquitinated proteins. After overexpression of Malt1, impaired autophagy activation caused by Card9 deficient was significantly rescued. Together, our results indicate that Card9 protects fungal peritonitis by regulating Malt1-mediated autophagy in macrophages. Our research provides a new idea for the pathogenesis of fungal peritonitis, which is of great significance for the clinical treatment of fungal peritonitis.

Card9 protects sepsis by regulating Ripk2-mediated activation of NLRP3 inflammasome in macrophages.

Sepsis is characterized by systemic inflammation, it's caused by primary infection of pathogenic microorganisms or secondary infection of damaged tissue. In this study, we focus on sepsis-induced intestine barrier functional disturbalice, presenting as increased permeability of intestinal epithelium. We observed that the phenotype of LPS-induced sepsis was exacerbated in Card9-/- mice, especially displaying more serious intestinal inflammation and gut barrier dysfunction. Next, we found the hyperactivation of NLRP3 inflammasome in the intestinal macrophages of Card9-/--sepsis mice. Moreover, Card9 over-expression decreased NLRP3 inflammasome activation in macrophages. Furthermore, we found that Card9 inhibited NLRP3 inflammasome activation by recruiting Ripk2. The competitive binding between Ripk2 with Caspase-1, instead of ASC with Caspase-1, inhibited the NLRP3 inflammasome activation. Over-expression of Ripk2 alleviated septic intestinal injury caused by Card9 deficiency. Taken together, we suggested Card9 acts as a negative regulation factor of NLRP3 inflammasome activation, which protects against intestinal damage during sepsis. Therefore, maintaining Card9-Ripk2 signaling homeostasis may provide a novel therapy of septic intestinal damage.

Bornlisy Attenuates Colitis-Associated Colorectal Cancer via Inhibiting GPR43-Mediated Glycolysis.

There is evidence that probiotics have a broad antitumor effect in colorectal cancer (CRC). However, the mechanism remains obscure. Here, we investigated the effect of Bornlisy (BO)-cocktails of three probiotics on colitis-associated colon cancer (CAC) and the underlying mechanism. The treatment of CAC mice with BO resulted in decreased tumor loads as compared with their counterparts. BO also inhibited the proliferation and metastasis of CRC cells in vitro. Furthermore, BO inhibited cell proliferation through downregulating glycolysis. Activating glycolysis reversed the protective role of BO in the CAC mice. Mechanically, BO administration promoted the activation of GPR43, followed by its downstream PLC-PKC-ERK pathway, which led to decreased glucose metabolism. These results suggest that BO may provide an intervention strategy for CRC therapy, while GPR43 is a potential targeting receptor during the BO treatment.