Cardiolipin activates antigen-presenting cells via TLR2-PI3K-PKN1-AKT/p38-NF-kB signaling to prime antigen-specific naïve T cells in mice.

Mitochondrial defects and antimitochondrial cardiolipin (CL) antibodies are frequently detected in autoimmune disease patients. CL from dysregulated mitochondria activates various pattern recognition receptors, such as NLRP3. However, the mechanism by which mitochondrial CL activates APCs as a damage-associated molecular pattern to prime antigen-specific naïve T cells, which is crucial for T-cell-dependent anticardiolipin IgG antibody production in autoimmune diseases is unelucidated. Here, we show that CL increases the expression of costimulatory molecules in CD11c+ APCs both in vitro and in vivo. CL activates CD11c+ APCs via TLR2-PI3K-PKN1-AKT/p38MAPK-NF-κB signaling. CD11c+ APCs that have been activated by CL are sufficient to prime H-Y peptide-specific naïve CD4+ T cells and OVA-specific naïve CD8+ T cells. TLR2 is necessary for anti-CL IgG antibody responses in vivo. Intraperitoneal injection of CL does not activate CD11c+ APCs in CD14 KO mice to the same extent as in wild-type mice. CL binds to CD14 (Kd = 7 × 10-7 M). CD14, but not MD2, plays a role in NF-kB activation by CL, suggesting that CD14+ macrophages contribute to recognizing CL. In summary, CL activates signaling pathways in CD11c+ APCs through a mechanism similar to gram (+) bacteria and plays a crucial role in priming antigen-specific naïve T cells.

Blackcurrant Alleviates Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice.

Previous studies have reported that anthocyanin (ACN)-rich materials have beneficial effects on ulcerative colitis (UC). Blackcurrant (BC) has been known as one of the foods rich in ACN, while studies demonstrating its effect on UC are rare. This study attempted to investigate the protective effects of whole BC in mice with colitis using dextran sulfate sodium (DSS). Mice were orally given whole BC powder at a dose of 150 mg daily for four weeks, and colitis was induced by drinking 3% DSS for six days. Whole BC relieved symptoms of colitis and pathological changes in the colon. The overproduction of pro-inflammatory cytokines such as IL-1ß, TNF-α, and IL-6 in serum and colon tissues was also reduced by whole BC. In addition, whole BC significantly lowered the levels of mRNA and protein of downstream targets in the NF-κB signaling pathway. Furthermore, BC administration increased the expression of genes related to barrier function: ZO-1, occludin, and mucin. Moreover, the whole BC modulated the relative abundance of gut microbiota altered with DSS. Therefore, the whole BC has demonstrated the potential to prevent colitis through attenuation of the inflammatory response and regulation of the gut microbial composition.

Kimchi and Leuconostoc mesenteroides DRC 1506 Alleviate Dextran Sulfate Sodium (DSS)-Induced Colitis via Attenuating Inflammatory Responses.

Ulcerative colitis (UC) is caused by inflammation only in the mucosa of the colon, and its incidence is increasing worldwide. The intake of probiotics is known to have a beneficial effect on the development of UC. In this study, we investigated the alleviating effects of kimchi (KC), a fermented food rich in probiotics, and Leuconostoc mesenteroides DRC 1506 (DRC) isolated from kimchi on UC. A freeze-dried kimchi suspension and DRC were orally given to mice at a dose of 1 × 109 CFU/day for 3 weeks. Furthermore, 3% dextran sulfate sodium (DSS) in drinking water was given to induce UC. The KC and DRC groups reduced symptoms of colitis, such as disease activity index, decrease in colon length, colon weight-to-length ratio, and pathological damage to the colon caused by DSS treatment. The KC and DRC groups decreased the levels of pro-inflammatory cytokine (TNF-α) and increased anti-inflammatory cytokine (IL-10) in the colon tissues. At the mRNA and protein expression levels in the colon tissue, KC and DRC groups downregulated inflammatory factors and upregulated tight junction-related factors. Therefore, DRC, as well as KC supplementation, are potent in alleviating UC by improving the inflammatory response and mucosal barrier function in the colon.

Protective Effect of Gochujang on Inflammation in a DSS-Induced Colitis Rat Model.

Gochujang is a traditional Korean fermented soy-based spicy paste made of meju (fermented soybean), red pepper powder, glutinous rice, and salt. This study investigated the anti-inflammatory effects of Gochujang containing salt in DSS-induced colitis. Sprague-Dawley (SD) rats were partitioned into five groups: normal control, DSS control, DSS + salt, DSS + mesalamine, and DSS + Gochujang groups. They were tested for 14 days. Gochujang improved the disease activity index (DAI), colon weight/length ratio, and colon histomorphology, with outcomes similar to results of mesalamine administration. Moreover, Gochujang decreased the serum levels of IL-1ß and IL-6 and inhibited TNF-α, IL-6, and IL-1ß mRNA expression in the colon. Gochujang downregulated the expression of iNOS and COX-2 and decreased the activation of NF-κB in the colon. Gochujang induced significant modulation in gut microbiota by significantly increasing the number of Akkermansia muciniphila while decreasing the numbers of Enterococcus faecalis and Staphylococcus sciuri. However, compared with the DSS group, the salt group did not significantly change the symptoms of colitis or cytokine levels in serum and colon. Moreover, the salt group significantly decreased the gut microflora diversity. Gochujang mitigated DSS-induced colitis in rats by modulating inflammatory factors and the composition of gut microflora, unlike the intake of salt alone.

TLR4-independent and PKR-dependent interleukin 1 receptor antagonist expression upon LPS stimulation.

Dendritic cells (DCs) induce innate immune responses by recognizing bacterial LPS through TLR4 receptor complexes. In this study, we compared gene expression profiles of TLR4 knockout (TLR4(neg)) DCs and wild type (TLR4(pos)) DCs after stimulating with LPS. We found that the expression of various inflammatory genes by LPS were TLR4-independent. Among them, interleukin 1 receptor antagonist (IL-1rn) was of particular interest since IL-1rn is a potent natural inhibitor of proinflammatory IL-1. Using RT-PCR, real-time PCR, immunoblotting and ELISA, we demonstrated that IL-1rn was induced by DCs stimulated with LPS in the absence of TLR4. 2-Aminopurine, a pharmacological PKR inhibitor, completely abrogated LPS-induced expression of IL-1rn in TLR4(neg) DCs, suggesting that LPS-induced TLR4-independent expression of IL-1rn might be mediated by PKR pathways. Considering that IL-1rn is a physiological inhibitor of IL-1, TLR4-independent and PKR-dependent pathways might be crucial in counter-balancing proinflammatory effector functions of DCs resulted from TLR4-dependent activation by LPS.

Taurodeoxycholate Increases the Number of Myeloid-Derived Suppressor Cells That Ameliorate Sepsis in Mice.

Bile acids (BAs) control metabolism and inflammation by interacting with several receptors. Here, we report that intravenous infusion of taurodeoxycholate (TDCA) decreases serum pro-inflammatory cytokines, normalizes hypotension, protects against renal injury, and prolongs mouse survival during sepsis. TDCA increases the number of granulocytic myeloid-derived suppressor cells (MDSCLT) distinctive from MDSCs obtained without TDCA treatment (MDSCL) in the spleen of septic mice. FACS-sorted MDSCLT cells suppress T-cell proliferation and confer protection against sepsis when adoptively transferred better than MDSCL. Proteogenomic analysis indicated that TDCA controls chromatin silencing, alternative splicing, and translation of the immune proteome of MDSCLT, which increases the expression of anti-inflammatory molecules such as oncostatin, lactoferrin and CD244. TDCA also decreases the expression of pro-inflammatory molecules such as neutrophil elastase. These findings suggest that TDCA globally edits the proteome to increase the number of MDSCLT cells and affect their immune-regulatory functions to resolve systemic inflammation during sepsis.

Ethanolic extract of seabuckthorn (Hippophae rhamnoides L) prevents high-fat diet-induced obesity in mice through down-regulation of adipogenic and lipogenic gene expression.

Phenolic compounds and flavonoids ameliorate bodyweight, blood glucose, and serum lipid profile. Since seabuckthorn (Hippophae rhamnoides L.) is known as a rich source of isoflavones and flavonoids, we hypothesized that ethanolic extract of seabuckthorn leaves (SL) may have anti-obesity and hypoglycemic effects. To investigate the effect of ethanolic extract of SL, 32 C57BL/6J mice were randomly divided into 4 dietary groups, containing 8 mice in each group: normal diet group; high-fat diet (HD) control group; high-fat diet with SL extract, 500 mg/kg body weight (BW) (SL1) group; and high-fat diet with SL extract, 1000 mg/kg BW (SL2) group. After 13 weeks, it was observed that oral administration of SL extract significantly reduced the energy intake; BW gain; epididymal fat pad weight; hepatic triglyceride, hepatic, and serum total cholesterol levels; and serum leptin levels in the SL groups compared to the HD group. However, differences in serum triglyceride and insulin levels in the SL groups were not significant in comparison to the HD group. The hepatic mRNA expression of peroxisome proliferator-activated receptor (PPAR) α and carnitine palmitoyltransferase 1 along with PPAR-γ were significantly increased in SL groups, whereas the level of acetyl-CoA carboxylase was significantly reduced in SL groups compared to HD group. Our results indicated that SL is effective in preventing BW gain and fat accumulation in the liver; it also reduced adipose tissue mass, hepatic lipid profile, and serum leptin level in the mouse. Together, these observations suggest that SL is a potential agent to study in the management of obesity and related disorders.