Overturning M2 phenotype macrophage polarization is a promising therapeutic strategy for gastric cancer (GC). Diosmetin (DIO) is a natural flavonoid with antitumor effect. The aim of this study was to investigate the effect of DIO on polarization of M2 phenotype macrophages in GC. THP‐1 cells were induced to M2 phenotype macrophages and co‐cultured with AGS cells. The effects of DIO were determined by flow cytometry, qRT‐PCR, CCK‐8, Transwell, and western blot. To explore the mechanisms, THP‐1 cells were transfected with adenoviral vectors containing tumor necrosis factor receptor‐associated factor 2 (TRAF2) or si‐TRAF2. DIO (0, 5, 10, and 20 μM) restrained the M2 phenotype macrophage polarization. In addition, DIO (20 μM) reversed the increased viability and invasion of AGS cells induced by the co‐culture of M2 macrophages. Mechanistically, TRAF2 knockdown inhibited the effect of M2 phenotype macrophages on AGS cells' growth and invasion. Furthermore, DIO (20 μM) was found to decrease TRAF2/NF‐κB activity in GC cells. However, TRAF2 overexpressed reversed the inhibitory effect of DIO on the co‐culture system. The in vivo study confirmed that DIO treatment (50 mg/kg) could repress the growth of GC. DIO treatment markedly reduced the expressions of Ki‐67 and N‐cadherin, and decreased the protein levels of TRAF2 and p‐NF‐κB/NF‐κB. In conclusion, DIO inhibited the growth and invasion of GC cells by interfering with M2 phenotype macrophage polarization through repression of the TRAF2/NF‐κB signaling pathway.

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Interferons and chemokines-mediated immune responses are two general antiviral programs of the innate immune system in response to viral infections and have recently emerged as important players in systemic metabolism. In this study, we found that the chemokine CCL4 is negatively regulated by glucose metabolism and avian leukosis virus subgroup J (ALV-J) infection in chicken macrophages. This immune response is defined by low expression levels of CCL4 by high glucose treatment or ALV-J infection. Moreover, the ALV-J envelope protein is responsible for CCL4 inhibition. We further confirmed that CCL4 can inhibit glucose metabolism and ALV-J replication in chicken macrophages. The present study provides novel insights into the antiviral defence mechanism and metabolic regulation of the chemokine CCL4 in chicken macrophages.

Interferon and chemokine-mediated immune responses are two general antiviral programs of the innate immune system in response to viral infections and have recently emerged as important players in systemic metabolism. This study found that the chemokine CCL4 is negatively regulated by glucose metabolism and avian leukosis virus subgroup J (ALV-J) infection in chicken macrophages. Low expression levels of CCL4 define this immune response to high glucose treatment or ALV-J infection. Moreover, the ALV-J envelope protein is responsible for CCL4 inhibition. We confirmed that CCL4 could inhibit glucose metabolism and ALV-J replication in chicken macrophages. The present study provides novel insights into the antiviral defense mechanism and metabolic regulation of the chemokine CCL4 in chicken macrophages.

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections dating back many millions of years, and their derived transcripts with viral signatures are important sources of long noncoding RNAs (lncRNAs). We have previously shown that the chicken ERV-derived lncRNA lnc-ALVE1-AS1 exerts antiviral innate immunity in chicken embryo fibroblasts. However, it is not clear whether this endogenous retroviral RNA has a similar function in immune cells. Here, we found that lnc-ALVE1-AS1 was persistently inhibited in chicken macrophages after avian leukosis virus subgroup J (ALV-J) infection. Furthermore, overexpression of lnc-ALVE1-AS1 significantly inhibited the proliferation of exogenous ALV-J, whereas knockdown of lnc-ALVE1-AS1 promoted the proliferation of ALV-J in chicken macrophages. This phenomenon is attributed to the induction of antiviral innate immunity by lnc-ALVE1-AS1 in macrophages, whereas knockdown of lnc-ALVE1-AS1 had the opposite effect. Mechanistically, lnc-ALVE1-AS1 can be sensed by the cytosolic pattern recognition receptor TLR3 and trigger the type I interferons response. The present study provides novel insights into the antiviral defense of ERV-derived lncRNAs in macrophages and offers new strategies for future antiviral solutions.