This review presents evidence that dual targeting of CCR2 and CCR5 has greater therapeutic potential than targeting either receptor alone.
A cardinal feature of inflammation is the tissue recruitment ...of leukocytes, a process that is mediated predominantly by chemokines via their receptors on migrating cells. CCR2 and CCR5, two CC chemokine receptors, are important players in the trafficking of monocytes/macrophages and in the functions of other cell types relevant to disease pathogenesis. This review provides a brief overview of the biological actions of CCR2 and CCR5 and a comprehensive summary of published data that demonstrate the involvement of both receptors in the pathogenesis of immunologic diseases (RA, CD, and transplant rejection) and cardiovascular diseases (atherosclerosis and AIH). In light of the potential for functional redundancy of chemokine receptors in mediating leukocyte trafficking and the consequent concern over insufficient efficacy offered by pharmacologically inhibiting one receptor, this review presents evidence supporting dual targeting of CCR2 and CCR5 as a more efficacious strategy than targeting either receptor alone. It also examines potential safety issues associated with such dual targeting.
T-cells are crucial in maintanence of intestinal homeostasis, however, it is still unclear how microbiota metabolites regulate T-effector cells. Here we show gut microbiota-derived short-chain fatty ...acids (SCFAs) promote microbiota antigen-specific Th1 cell IL-10 production, mediated by G-protein coupled receptors 43 (GPR43). Microbiota antigen-specific Gpr43
CBir1 transgenic (Tg) Th1 cells, specific for microbiota antigen CBir1 flagellin, induce more severe colitis compared with wide type (WT) CBir1 Tg Th1 cells in Rag
recipient mice. Treatment with SCFAs limits colitis induction by promoting IL-10 production, and administration of anti-IL-10R antibody promotes colitis development. Mechanistically, SCFAs activate Th1 cell STAT3 and mTOR, and consequently upregulate transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1), which mediates SCFA-induction of IL-10. SCFA-treated Blimp1
Th1 cells produce less IL-10 and induce more severe colitis compared to SCFA-treated WT Th1 cells. Our studies, thus, provide insight into how microbiota metabolites regulate Th1 cell functions to maintain intestinal homeostasis.
The antimicrobial peptides (AMP) produced by intestinal epithelial cells (IEC) play crucial roles in the regulation of intestinal homeostasis by controlling microbiota. Gut microbiota has been shown ...to promote IEC expression of RegIIIγ and certain defensins. However, the mechanisms involved are still not completely understood. In this report, we found that IEC expression levels of RegIIIγ and β-defensins 1, 3, and 4 were lower in G protein-coupled receptor (GPR)43
mice compared to that of wild-type (WT) mice. Oral feeding with short-chain fatty acids (SCFA) promoted IEC production of RegIIIγ and defensins in mice. Furthermore, SCFA induced RegIIIγ and β-defensins in intestinal epithelial enteroids generated from WT but not GPR43
mice. Mechanistically, SCFA activated mTOR and STAT3 in IEC, and knockdown of mTOR and STAT3 impaired SCFA induction of AMP production. Our studies thus demonstrated that microbiota metabolites SCFA promoted IEC RegIIIγ and β-defensins in a GPR43-dependent manner. The data thereby provide a novel pathway by which microbiota regulates IEC expression of AMP and intestinal homeostasis.
Phytolacca americana L. (pokeweed) has metal phytoremediation potential, but little is known about its metal accumulation-related genes. In this study, the de novo sequencing of total RNA produced ...53.15 million reads covering 10.63 gigabases of transcriptome raw data in cadmium (Cd)-treated and untreated pokeweed. Of the 97,502 assembled unigenes, 42,197 had significant matches in a public database and were annotated accordingly. An expression level comparison between the samples revealed 1515 differentially expressed genes (DEGs), 923 down- and 592 up-regulated under Cd treatment. A KEGG pathway enrichment analysis of DEGs revealed that they were involved in 72 metabolism pathways, with photosynthesis, phenylalanine metabolism, ribosome, phenylpropanoid biosynthesis, flavonoid biosynthesis and carbon fixation in photosynthetic organisms containing 24, 18, 72, 14, 7 and 15 genes, respectively. Genes related to heavy metal tolerance, absorption, transport and accumulation were also identified, including 11 expansins, 8 nicotianamine synthases, 6 aquaporins, 4 ZRT/IRT-like proteins, 3 ABC transporters and 3 metallothioneins. The gene expression results of 12 randomly selected DEGs were validated using quantitative real-time PCR, and showed different response patterns to Cd in their roots, stems and leaves. These results may be helpful in increasing our understanding of heavy metal hyperaccumulators and in future phytoremediation applications.
It has been shown recently that neutrophils are able to produce IL-22 and IL-17, which differentially regulate the pathogenesis of inflammatory bowel disease. However, it is still largely unknown how ...the neutrophil production of IL-22 and IL-17 is regulated, and their role in the pathogenesis of inflammatory bowel disease. In this study, we found that IL-23 promoted neutrophil production of IL-17 and IL-22. IL-23 stimulated the neutrophil expression of IL-23R as well as rorc and ahr. Retinoid acid receptor-related orphan receptor γ t and aryl-hydrocarbon receptor differentially regulated IL-23 induction of neutrophil IL-17 and IL-22. In addition, IL-23 induced the activation of mTOR in neutrophils. Blockade of the mTOR pathway inhibited IL-23-induced expression of rorc and ahr, as well as IL-17 and IL-22 production. By using a microbiota Ag-specific T cell-mediated colitis model, we demonstrated that depletion of neutrophils, as well as blockade of IL-22, resulted in a significant increase in the severity of colitis, thereby indicating a protective role of neutrophils and IL-22 in chronic colitis. Collectively, our data revealed that neutrophils negatively regulate microbiota Ag-specific T cell induction of colitis, and IL-23 induces neutrophil production of IL-22 and IL-17 through induction of rorc and ahr, which is mediated by the mTOR pathway.
The gut microbiota has been shown critical for mucosal adjuvant activity of cholera toxin (CT), a potent mucosal adjuvant. However, the mechanisms involved remain largely unknown. In this study, we ...report that depletion of gut bacteria significantly decreased mucosal and systemic Ab responses in mice orally immunized with OVA and CT. Feeding mice short-chain fatty acids (SCFAs) promoted Ab responses elicited by CT, and, more importantly, rescued Ab responses in antibiotic-treated mice. In addition, mice deficient in GPR43, a receptor for SCFAs, showed impaired adjuvant activity of CT. Administering CT did not promote SCFA production in the intestines; thus, SCFAs facilitated but did not directly mediate the adjuvant activity of CT. SCFAs promoted B cell Ab production by promoting dendritic cell production of BAFF and ALDH1a2, which induced B cell expression of IFN regulatory factor 4, Blimp1, and XBP1, the plasma B cell differentiation-related genes. Furthermore, when infected with
GPR43
mice exhibited decreased Ab responses and were more susceptible to infection, whereas the administration of SCFAs promoted intestinal Ab responses in wild-type mice. Our study thereby demonstrated a critical role of gut microbiota and their metabolite SCFAs in promoting mucosal adjuvant activity of CT through GPR43.
(1) Background: With new potential drug targets emerging, combination therapies appear attractive to treat non-alcoholic steatohepatitis (NASH) and fibrosis. Chemokine receptor CCR2/5 antagonists can ...improve fibrosis by reducing monocyte infiltration and altering hepatic macrophage subsets. Fibroblast growth factor 21 (FGF21) may improve NASH by modulating lipid and glucose metabolism. We compared effects of single drug to combination treatment as therapeutic strategies against NASH. (2) Methods: We analyzed serum samples and liver biopsies from 85 nonalcoholic fatty liver disease (NAFLD) patients. A CCR2/5 inhibitor (BMS-687681-02-020) and a pegylated FGF21 agonist (BMS-986171) were tested in male C57BL/6J mice subjected to dietary models of NASH and fibrosis (choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) up to 12 weeks; short- (2w) or long-term (6w) treatment). (3) Results: In NAFLD patients, chemokine CCL2 and FGF21 serum levels correlated with inflammatory serum markers, only CCL2 was significantly associated with advanced liver fibrosis. In rodent NASH, CCR2/5 inhibition significantly reduced circulating Ly6C+ monocytes and hepatic monocyte-derived macrophages, alongside reduced hepatic inflammation and fibrosis. FGF21 agonism decreased body weight, liver triglycerides and histological NASH activity. Combination treatment reflected aspects of both compounds upon short- and long-term application, thereby amplifying beneficial effects on all aspects of steatohepatitis and fibrosis. (4) Conclusions: CCR2/5 inhibition blocks hepatic infiltration of inflammatory monocytes, FGF21 agonism improves obesity-related metabolic disorders. Combined therapy ameliorates steatohepatitis and fibrosis more potently than single drug treatment in rodent NASH, corroborating the therapeutic potential of combining these two approaches in NASH patients.
Lead (Pb) exposure is a well-established risk factor for dyslipidemia, and people are exposed to it in multiple ways daily. Dietary fiber is presumed to improve lipid metabolism disorders, but it is ...still unknown whether it can relieve the detrimental impact of Pb on dyslipidemia. We used publicly accessible data from the 2011–2016 cycles of the National Health and Nutrition Examination Survey (NHANES). A total of 2128 US adults were enrolled for the subsequent analysis. Heavy metal concentrations in blood were measured using inductively coupled plasma mass spectrometry (ICP-MS). A weighted logistic regression was conducted to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The dose–response relationship between blood heavy metals and dyslipidemia was explored using a weighted restricted cubic spline (RCS) analysis. After fully adjusting for potential confounding factors (age, gender, race, education level, ratio of family income to poverty, marital status, body mass index, physical activity, waist circumference, smoke, alcohol drinking and history of metabolic syndrome, hypertension, and diabetes), a positive association between blood Pb levels and dyslipidemia risk was revealed (OR = 1.20, 95% CI: 1.03–1.40). Dietary fiber intake may significantly modify the association between blood Pb levels and dyslipidemia (p-interaction = 0.049), with a stronger association (OR = 1.26, 95% CI: 1.05–1.52) being revealed in individuals with an inadequate intake of dietary fiber (<14 g/1000 kcal/day), but a null association (OR = 1.01, 95% CI: 0.72–1.42) being observed in those with an adequate intake of dietary fiber (≥14 g/1000 kcal/day). Moreover, the weighted RCS analysis showed that compared with the average blood Pb exposure level (4.24 µg/dL), a lower blood Pb exposure level (3.08 µg/dL) may contribute to the risk of dyslipidemia in the group with an inadequate dietary fiber intake. Our findings suggest that Pb exposure in blood may be a risk factor for dyslipidemia. However, an adequate dietary fiber intake may offset the risk of dyslipidemia caused by blood Pb exposure. Since avoiding Pb exposure in daily life is difficult, increasing dietary fiber intake in the future might be a promising approach to alleviate dyslipidemia caused by Pb exposure.
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