PtdIns3P phosphatases MTMR3 and MTMR4 negatively regulate innate immune responses to DNA through modulating STING trafficking.

The innate immune system plays an essential role in initial recognition of pathogen infection by producing inflammatory cytokines and type I interferons. cGAS is a cytoplasmic sensor for DNA derived from DNA viruses. cGAS binding with DNA induces the production of cGAMP, a second messenger that associates with STING in endoplasmic reticulum (ER). STING changes its cellular distribution from ER to perinuclear Golgi, where it activates the protein kinase TBK1 that catalyzes the phosphorylation of IRF3. Here we found that STING trafficking is regulated by myotubularin-related protein (MTMR) 3 and MTMR4, members of protein tyrosine phosphatases that dephosphorylate 3' position in phosphatidylinositol (PtdIns) and generate PtdIns5P from PtdIns3,5P2 and PtdIns from PtdIns3P. We established MTMR3 and MTMR4 double knockout (DKO) RAW264.7 macrophage cells and found that they exhibited increased type I interferon production after interferon-stimulatory DNA (ISD) stimulation and herpes simplex virus 1 infection concomitant with enhanced IRF3 phosphorylation. In DKO cells, STING rapidly trafficked from ER to Golgi after ISD stimulation. Notably, DKO cells exhibited enlarged cytosolic puncta positive for PtdIns3P and STING was aberrantly accumulated in this puncta. Taken together, these results suggest that MTMR3 and MTMR4 regulate the production of PtdIns3P, which plays a critical role in suppressing DNA-mediated innate immune responses via modulating STING trafficking.

Long-term follow-up of the effects of a school-based caries preventive programme involving fluoride mouth rinse and targeted fissure sealant: evaluation at 20 years old.

AIMS: The evaluation of long-term effects five years after the completion of a school-based caries prevention programme combined with fluoride mouth rinse (FMR) and targeted sealant application (TS). PARTICIPANTS: 46 subjects in the FMR+TS group and 55 subjects in the FMR group, who were 20 -21 years old, were analysed. They had participated in each 11-year programme, underwent a dental examination at the age of 20 years and answered a self-administered questionnaire. METHODS: The caries prevalence and mean DMFT were calculated, and differences between the two groups were analysed by the chi2 test and Mann-Whitney test, respectively. Logistic and multiple regression analyses were performed using sex, group, and five questionnaire items as independent variables. RESULTS: The caries prevalence and mean DMFT (SD) was 28.3%, 1.56 (3.00) in the FMR+TS group and 60.0%, 2.20 (2.44) in the FMR group, and the difference was significant respectively. In the logistic regression analysis the odds ratio of the FMR+TS group to the FMR group was 0.28 (p < 0.05). CONCLUSIONS: The caries-preventive effects of a school-based combined programme with FMR and TS continued for more than five years after the programme until the age of 20 years.

Renal function and periodontal disease in elderly Japanese.

BACKGROUND: Chronic renal failure involves a slow, progressive loss of renal function over months or years. It is possible that periodontal disease and chronic kidney disease might share common risk factors. This study investigated whether a link exists between periodontal disease and chronic renal function in community-dwelling elderly subjects. METHODS: A total of 145 study subjects, all 77 years of age, participated in this study. A periodontal examination was carried out by trained dentists. Urine was collected over 24 hours, and blood was taken on the morning of the dental exam. The volume of creatinine per 24 hours (Cre_U) and volume of urine per 24 hours were used as urinary markers of kidney function; serum creatinine levels (Cre_S) were used as a blood marker of kidney function. Creatinine clearance per 24 hours was calculated as Cre_U/Cre_S. In addition, biochemical parameters of bone turnover were measured: urinary deoxypyridinoline (U-DPD) as a bone resorption marker and serum osteocalcin (S-OC) as a bone formation marker. Multiple regression analysis was used to evaluate the relationship between the percentage of periodontal sites with > or =6-mm clinical attachment level (% > or =6-mm CAL) and renal function, as well as the relationship between % > or =6-mm CAL and bone metabolism. The % > or =6-mm CAL was used as the dependent variable. The number of remaining teeth, smoking habit, gender, use of interdental brushes or dental floss, volume of urine per 24 hours, and creatinine clearance per 24 hours were independent variables in the first test. In addition, the number of remaining teeth, smoking habits, gender, use of interdental brushes or dental floss, U-DPD, and S-OC were independent variables in the second test. RESULTS: Multiple regression analysis showed that creatinine clearance per 24 hours and S-OC were significantly associated with % > or =6-mm CAL per person. The standardized coefficients were 0.26 (P = 0.015) and -0.27 (P = 0.006), respectively. CONCLUSIONS: The % > or =6-mm CAL was significantly associated with renal function and bone metabolism markers. This study suggests that the increased incidence of chronic renal failure that occurs with age might increase the probability of severe periodontal disease in community-dwelling elderly subjects.