Metabolism is a critical immune regulator under physiologic and pathologic conditions. Culminating evidence has disentangled the contribution of distinct metabolic pathways, namely glucolysis, pentose phosphate, fatty acid oxidation, glutaminolysis, Krebs cycle and oxidative phosphorylation, in modulating innate and adaptive immune cells based on their activation/differentiation state. Metabolic aberrations and changes in the intracellular levels of specific metabolites are linked to the inflammatory phenotype of immune cells implicated in autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and diabetes. Notably, targeting metabolism such as the mTOR by rapamycin, hexokinase by 2-deoxy-D-glucose, AMP-activated protein kinase by metformin, may be used to ameliorate autoimmune inflammation. Accordingly, research in immunometabolism is expected to offer novel opportunities for monitoring and treating immune-mediated diseases.

Objectives: Asymptomatic bacteriuria (ASB) is a common finding in patients with diabetes. Moreover, patients with diabetes and ASB have a greater risk for symptomatic urinary tract infections and associated severe complications. The aim of this study was to estimate the prevalence of ASB, as well as to identify independent risk factors and related pathogens associated with ASB in female and male patients with type 2 diabetes mellitus (T2D). Methods: This prospective case-control study was performed at the University hospital, and the Venezeleion General Hospital, Heraklion, Greece between 2012 and 2019. All patients with T2D attending the diabetes and hypertension outpatient clinics at both hospitals were enrolled, and data regarding their medical history and clinical and laboratory profiles were recorded. Asymptomatic patients with positive urine cultures were assigned as cases while those with negative urine cultures were designated as controls. Results: A total of 437 adult patients of which 61% were female and 39% were male patients with a mean age of 70.5 ± 9.6 years, were enrolled. The prevalence of ASB was 20.1%, in total. ASB was noted in 27% of female participants and 9.4% of male participants. Higher glycated hemoglobin (OR = 3.921, 95%CI: 1.521–10.109, p < 0.001) and urinary tract infection within the previous year (OR = 13.254, 95%CI: 2.245–78.241, p < 0.001) were independently positively associated with ASB, while higher levels of vitamin B12 were independently negatively associated with ASB (OR = 0.994 per ng/mL, 95%CI: 0.989–0.999, p < 0.001). Conclusions: Development of ASB was associated with specific factors, some of which may be modifiable. Interestingly, high B12 was found to be negatively associated with ASB.

It is becoming increasingly appreciated that the non-coding genome may have a great impact on the regulation of chromatin structure and gene expression. The innate immune response can be mediated upon lipopolysaccharide stimulation of macrophages which leads to immediate transcriptional activation of early responsive genes including tumor necrosis factor alpha (Tnfα). The functional role of non-coding RNAs, such as lncRNAs and microRNAs, on the transcriptional activation of proinflammatory genes and the subsequent regulation of the innate immune response is still lacking mechanistic insights. In this study we wanted to unravel the functional role of the lncRNA SeT, which is encoded from the murine Tnfα gene locus, and miR-155 on the transcriptional regulation of the Tnfα gene. We utilized genetically modified mice harboring either a deletion of the SeT promoter elements or the mature miR-155 and studied the response of macrophages to lipopolysaccharide (LPS) stimulation. We found that decreased expression of the lncRNA SeT in murine primary macrophages resulted in increased mortality of mice challenged with LPS, which was corroborated by increased Tnfα steady state mRNA levels and a higher frequency of biallelically expressing macrophages. On the contrary, miR-155 deletion resulted in reduced Tnfα mRNA levels supported by a lower frequency of biallelically expressing macrophages upon stimulation with LPS. In both cases, in the absence of either lncRNA SeT or miR-155 we observed a deregulation of the Tnfα allele homologous pairing, previously shown to regulate the switch from mono- to bi-allelic gene expression. Although lncRNA SeT was not found to be a direct target of miR-155 its stability was increased upon miR-155 deletion. This study suggests a role of the non-coding genome in mediating Tnfα mRNA dosage control based on the regulation of homologous pairing of gene alleles and their subsequent biallelic expression.