Publications

Inflammation is an important driver of atherosclerosis, and the favourable outcomes of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial revealed the large potential of anti-inflammatory drugs for the treatment of cardiovascular disease, especially in patients with a pro-inflammatory constitution. However, the complex immune reactions driving inflammation in the vascular wall in response to an atherosclerotic microenvironment are still being unravelled. Novel insights into the cellular processes driving immunity and inflammation revealed that alterations in intracellular metabolic pathways are strong drivers of survival, growth, and function of immune cells. Therefore, this position paper presents a brief overview of the recent developments in the immunometabolism field, focusing on its role in atherosclerosis. We will also highlight the potential impact of immunometabolic markers and targets in clinical cardiovascular medicine.

No abstract is provided for this article.

The initiating cause of Behçet's disease (BD) is unknown, but an aberrant response to infection has been suggested. In this study, single nucleotide polymorphisms in Toll-like receptors (TLRs) and associated molecules that have a sentinel function at mucosal surfaces were analysed in patients with BD.TLR expression was determined by immunohistochemistry in buccal mucosal tissue from patients with BD, in tissue from patients with lichen planus (LP) or pyogenic granuloma (PG) as disease controls, or from healthy individuals. Using SSP-PCR we analysed SNP in CD14, TLR2, TLR4 and TIRAP (TIR domain-containing adaptor protein) in patients with BD from different geographical regions.TLR expression was increased in buccal lesions from patients with BD compared with healthy controls; however, a similar increase was seen in lesion tissue from patients with LP or PG, suggesting that this was a generalized inflammatory response as opposed to a BD-specific response. SNP analysis showed no association between CD14, TLR2 or TLR4 polymorphisms. However, TIRAP 180Leu was significantly associated with BD in UK, but not Middle Eastern, patients.TLR expression showed no difference in tissue from patients with BD compared with either disease or healthy controls. Likewise, SNPs in TLR genes were no different from healthy controls. The association with the increased function variant of TIRAP suggests that encounter with a pathogen at mucosal sites will lead to increased cytokine production and tissue damage with persistence of mucosal lesions.

Atopic dermatitis (AD) is one of the most common skin diseases with a multifactorial etiology. Mutations leading to loss of skin barrier function are associated with the development of AD with group 2 innate lymphoid cells (ILC2) promoting acute skin inflammation. Filaggrin-mutant (Flg

Preterm birth, the major cause of neonatal mortality in developed countries, is associated with intrauterine infections and inflammation, although the exact mechanisms underlying this event are unclear. In this study, we show that circulating fetal DNA, which is elevated in pregnancies complicated by preterm labor or preeclampsia, triggers an inflammatory reaction that results in spontaneous preterm birth. Fetal DNA activates NF-κB, shown by IκBα degradation in human PBMCs resulting in production of proinflammatory IL-6. We show that fetal resorption and preterm birth are rapidly induced in mice after i.p. injection of CpG or fetal DNA (300 μg/dam) on gestational day 10–14. In contrast, TLR9−/− mice were protected from these effects. Furthermore, this effect was blocked by oral administration of the TLR9 inhibitor chloroquine. Our data therefore provide a novel mechanism for preterm birth and preeclampsia, highlighting TLR9 as a potential therapeutic target for these common disorders of pregnancy.

Different immune activation states require distinct metabolic features and activities in immune cells. For instance, inhibition of fatty acid synthase (FASN), which catalyzes the synthesis of long-chain fatty acids, prevents the proinflammatory response in macrophages; however, the precise role of this enzyme in this response remains poorly defined. Consistent with previous studies, we found here that FASN is essential for lipopolysaccharide-induced, Toll-like receptor (TLR)-mediated macrophage activation. Interestingly, only agents that block FASN upstream of acetoacetyl-CoA synthesis, including the well-characterized FASN inhibitor C75, inhibited TLR4 signaling, while those acting downstream had no effect. We found that acetoacetyl-CoA could overcome C75's inhibitory effect, whereas other FASN metabolites, including palmitate, did not prevent C75-mediated inhibition. This suggested an unexpected role for acetoacetyl-CoA in inflammation that is independent of its role in palmitate synthesis. Our evidence further suggested that acetoacetyl-CoA arising from FASN activity promotes cholesterol production, indicating a surprising link between fatty acid synthesis and cholesterol synthesis. We further demonstrate that this process is required for TLR4 to enter lipid rafts and facilitate TLR4 signaling. In conclusion, we have uncovered an unexpected link between FASN and cholesterol synthesis that appears to be required for TLR signal transduction and proinflammatory macrophage activation.

No abstract is provided for this article.

The majority of antibiotics are prescribed in primary care. Urinary tract infections (UTIs) are the second most common reason for antibiotic prescribing in this sector. This study explores activities used by English Clinical Commissioning Groups (CCGs) to improve UTI prevention and management 2017-2022. An online questionnaire was sent to CCG primary care chief nurses and medicines optimisation leads August-September 2022. Qualitative data was mapped to the Theoretical Domains Framework. Participant response rate was 14.1% (56/397), with representation from 29.2% (31/106) CCGs and across a range of roles. Education and training were the most reported intervention types, while changing the environment to facilitate behaviours was the least. Most interventions targeted general practice staff and patients, followed by care home staff, and residents and their families.The most reported success measures included reduction in antibiotic prescribing (54.5%, 97/178 interventions); positive stakeholder feedback (42.1%, 75/178); and increased adherence to diagnostic guidelines (32.6%, 58/178). 48.8% (20/41) stated their UTI activities had not been formally evaluated. Barriers and facilitators to intervention implementation included: availability of resources and time; staff collaboration; availability and accuracy of information; public and staff beliefs; systems and processes; and staff roles and responsibilities. UTI interventions rolled out through English health authorities could be further improved through structures that increase capacity to effectively evaluate activities and share learning. Staff engagement and collaboration are key facilitators to implementation and should be leveraged in further initiatives, while support and guidance are provided to adapt initiatives to fit in the changing healthcare landscape.

Helicobacter pylori infection results in peptic ulceration and chronic gastritis through mechanisms which are not fully elucidated. Live H. pylori activate the pro‐inflammatory transcription factor NF‐κB in gastric epithelial cells. Patients may have peptic ulcer disease in the absence of H. pylori infection; therefore other factors contribute to the inflammatory process. Maximal acid output in patients with H. pylori infection and duodenal ulceration is significantly increased indicating a role for acid in the pathogenesis of mucosal ulceration. The effect of low pH on NF‐κB activation in gastric epithelial cells has not been studied. Human gastric epithelial cells (AGS) were exposed to a range of pH changes in the presence or absence of H. pylori . NF‐κB DNA‐binding and cytosolic IκB‐α were measured using electrophoretic mobility shift assay and Western blotting. NF‐κB DNA‐binding in gastric epithelial cells dramatically increased when the pH of the culture medium decreased. Increases in NF‐κB nuclear binding were paralleled by decreasing amounts of cytosolic IκB‐α. These findings were similar but less potent than those observed when cells were exposed to H. pylori . Low pH resulted in enhancement of H. pylori ‐induced NF‐κB nuclear binding. DNA binding of NF‐κB activation secondary to low pH was attenuated by PD98059 but not by SB203580. Similar to H. pylori , low pH potently and independently augments NF‐κB nuclear binding in AGS cells and such activation appears to be mediated through MEK1‐dependant signaling pathways. © 2005 Wiley‐Liss, Inc.

The NLRP3 inflammasome controls IL-1β maturation in antigen presenting cells but a direct role in human adaptive immune cells has not been described. Here we show that the NLRP3 inflammasome assembles in human CD4+ T cells and initiates caspase-1-dependent IL-1b secretion, thereby promoting IFN-γ production and Th1 differentiation in an autocrine fashion. Importantly, NLRP3 assembly requires intracellular C5 activation and stimulation of C5a receptor 1 (C5aR1), which drive reactive oxygen species (ROS) production. The alternative cell surface expressed C5a receptor 2 (C5aR2) negatively regulates this process. Dysregulation of NLRP3 activity in T cells affects inflammatory responses in autoimmune disease or infection. Firstly, CD4+ T cells from patients with cryopyrin-associated periodic syndromes (CAPS), who have constitutively-active NLRP3, exhibit overactive Th1 responses that are normalized by NLRP3 inhibitor treatment. Secondly, IFN-γ production is impaired in T cells from Nlpr3−/− or Il1a/Il1b−/− mice upon viral infection. Our results demonstrate that NLRP3 inflammasome activity is not confined to ‘innate immune cells’ but is an integral component of normal adaptive Th1 responses.