Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20

Toll-like receptors (TLRs) on host cells are chronically engaged by microbial ligands during homeostatic conditions. These signals do not cause inflammatory immune responses in unperturbed mice, even though they drive innate and adaptive immune responses when combating microbial infections. A20 is a ubiquitin-modifying enzyme that restricts exogenous TLR-induced signals. We show that MyD88-dependent TLR signals drive the spontaneous T cell and myeloid cell activation, cachexia, and premature lethality seen in A20-deficient mice. We have used broad spectrum antibiotics to demonstrate that these constitutive TLR signals are driven by commensal intestinal flora. A20 restricts TLR signals by restricting ubiquitylation of the E3 ligase tumor necrosis factor receptor–associated factor 6. These results reveal both the severe proinflammatory pathophysiology that can arise from homeostatic TLR signals as well as the critical role of A20 in restricting these signals in vivo. In addition, A20 restricts MyD88-independent TLR signals by inhibiting Toll/interleukin 1 receptor domain–containing adaptor inducing interferon (IFN) β–dependent nuclear factor κB signals but not IFN response factor 3 signaling. These findings provide novel insights into how physiological TLR signals are regulated

NT-proBNP levels and mortality in a genera population-based cohort from Turkey: a long-term follow-up study

Aim: We investigated the relationship between NT-ProBNP and mortality in a general population-based cohort. Methods & Results: A total of 2021 out of 4650 participants from previously published HAPPY study were included. Mean follow-up was 84.5 +/- 10.4 months. After adjusting for risk factors, high levels of LogNT-proBNP predicted all-cause death (HR: 3.23; 95% CI: 2.20-4.75; p < 0.001) and cardiovascular death (HR: 3.85; 95% CI: 2.37-6.26; p < 0.001). Regression analysis revealed that LogNT-proBNP was an independent predictor of all-cause death (HR: 2.85; 95% CI: 1.91-4.24; p < 0.001) and cardiovascular death (HR: 3.02; 95% CI: 1.84-4.95; p < 0.001). Conclusion: Our study showed that in long term follow-up, NT-proBNP is associated with increased all-cause and cardiovascular mortalit

The Association between Serum Heme Oxygenase-1 Levels and Coronary SYNTAX Score

Aim: The relationship between heme oxygenase-1 (HO-1) levels and atherosclerosis was investigated in multiple studies. The aim of this study was to establish the relationship between HO-1 levels and coronary SYNergy between percutaneous coronary intervention with TAXus and Cardiac Surgery (SYNTAX) score in patients with stable coronary artery disease (CAD). Methods: Patients who had been planned to undergo invasive coronary angiography due to a suspected CAD, between the dates of September and December 2019, were included in the study. Serum HO-1 levels were measured from peripheral venous blood. The SYNTAX score was calculated using standard coronary angiography images. Regression analysis was performed to establish the relationship between HO-1 levels and the SYNTAX score. Results: In total, 137 patients were included. The median age was 63 years (IQR: 15), and most of the patients were male (75.2%). The median HO-1 level was 1.44 (IQR: 0.88) ng/mL, and the median SYNTAX score was 6 (IQR: 13). Regression analysis showed that HO-1 is the single most important variable associated with the SYNTAX score (HO-1 levels from 1.01 to 1.87 ng/mL, OR: 6.77, 95% confidence interval 5.18-8.36, p < 0.0001). Conclusion: In this study, serum HO-1 levels were significantly associated with the coronary SYNTAX score

The Ubiquitin Modifying Enzyme A20 Restricts B Cell Survival and Prevents Autoimmunity

SummaryA20 is a ubiquitin modifying enzyme that restricts NF-κB signals and protects cells against tumor necrosis factor (TNF)-induced programmed cell death. Given recent data linking A20 (TNFAIP3) with human B cell lymphomas and systemic lupus erythematosus (SLE), we have generated mice bearing a floxed allele of Tnfaip3 to interrogate A20's roles in regulating B cell functions. A20-deficient B cells are hyperresponsive to multiple stimuli and display exaggerated NF-κB responses to CD40-induced signals. Mice expressing absent or hypomorphic amounts of A20 in B cells possess elevated numbers of germinal center B cells, autoantibodies, and glomerular immunoglobulin deposits. A20-deficient B cells are resistant to Fas-mediated cell death, probably due to increased expression of NF-κB-dependent antiapoptotic proteins such as Bcl-x. These findings show that A20 can restrict B cell survival, whereas A20 protects other cells from TNF-induced cell death. Our studies demonstrate how reduced A20 expression predisposes to autoimmunity