Dietary Toll-like Receptor Stimulants Promote Hepatic Inflammation and Impair Reverse Cholesterol Transport in Mice via Macrophage-Dependent Interleukin-1 Production

Background: The mechanisms connecting dietary intake of processed foods with systemic inflammatory markers and cardiovascular risk remain poorly defined. We sought to compare the abundance of pro-inflammatory stimulants of innate immune receptors in processed foods with those produced by the murine ileal and caecal microbiota, and to explore the impact of their ingestion on systemic inflammation and lipid metabolism in vivo. Methods and results: Calibrated receptor-dependent reporter assays revealed that many processed foods, particularly those based on minced meats, contain pro-inflammatory stimulants of Toll-like receptor (TLR)-2 and TLR4 at concentrations which greatly exceed those produced by the endogenous murine ileal microbiota. Chronic dietary supplementation with these stimulants, at concentrations relevant to those measured in the Western diet, promoted hepatic inflammation and reduced several markers of reverse cholesterol transport (RCT) in mice. Hepatocytes were found to be insensitive to TLR2- and TLR4-stimulants directly, but their secretion of functional cholesterol acceptors was impaired by interleukin (IL)-1β released by TLR-responsive hepatic macrophages. Hepatic macrophage priming by high-fat diet enhanced the impairment of RCT by ingested endotoxin, and this was reversed by macrophage depletion via clodronate liposome treatment, or genetic deficiency in the IL-1 receptor. Conclusion: These findings reveal an unexpected mechanism connecting processed food consumption with cardiovascular risk factors, and introduce the food microbiota as a potential target for therapeutic regulation of lipid metabolism

Marginal zone B cells control the response of follicular helper T cells to a high-cholesterol diet

Splenic marginal zone B (MZB) cells, positioned at the interface between circulating blood and lymphoid tissue, detect and respond to blood-borne antigens. Here we show that MZB cells in mice activate a homeostatic program in response to a high-cholesterol diet (HCD) and regulate both the differentiation and accumulation of T follicular helper (TFH) cells. Feeding mice an HCD resulted in upregulated MZB cell surface expression of the immunoregulatory ligand PDL1 in an ATF3-dependent manner and increased the interaction between MZB cells and pre-TFH cells, leading to PDL1-mediated suppression of TFH cell motility, alteration of TFH cell differentiation, reduced TFH abundance and suppression of the proatherogenic TFH response. Our findings reveal a previously unsuspected role for MZB cells in controlling the TFH–germinal center response to a cholesterol-rich diet and uncover a PDL1-dependent mechanism through which MZB cells use their innate immune properties to limit an exaggerated adaptive immune response.This work was supported by BHF grant no. PG/15/76/31756, BHF grant no. PG/13/73/30466, ERC grant no. 2891164 and EC FP7 VIA grant no. HEALTH-F4- 2013-603131 to Z.M. and by SAF2013-45543-R from the Spanish Ministry of Economy and Competitiveness (MINECO) to J.L.d.l.P. M.N. was first supported by a Sara Borrell grant (CD09/00452) from the Instituto Nacional de Salud Carlos III (Spain) and then by a 2-year BHF Project Grant. M.N. has also received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. 608765. The Wellcome Trust supported the Cambridge Mouse Biochemistry Laboratory

Female genital mutilation in the Sudan: survey of the attitude of Khartoum university students towards this practice

Background: Female genital mutilation (FGM) or female circumcision is the removal of variable amounts of tissue from the female external genitalia. It is practised all over the world on very young girls. This study was conducted in Sudan where FGM is a criminal offence and not a religious dictate. We assessed the knowledge, attitudes, and perceptions of this practice among Khartoum university students and compared the differences between male and female student responses. Methods: An anonymised detailed questionnaire was distributed among the university students. In addition to the participant's age, marital status, course studying, details regarding their attitude, knowledge of the practice of FGM, and their own experiences were collected. Results: Of the 500 questionnaires distributed, 414 (82.8%) were returned from 192 (46%) females and 222 (54%) males. 109 (56.8%) of the female respondents were themselves circumcised.18.8% of the male students and 9.4% of the female students thought FGM was recommended by their religion. Only 90 (46.9%) female students compared with 133 (59.9%) male students thought FGM was illegal. Though 16 (8.3%) female respondents thought FGM would increase their chances of marriage, the majority, 166 (74.8%), of the male students would prefer a non-circumcised female. Conclusions: This study shows that 109 (56.8%) female university students who responded were circumcised. Confusing religious messages and ambiguous laws seem to be responsible for the continuation of this practice. The study highlights the partnership that needs to be established between religious leaders and educationalists to end this medieval practice