RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling.

The toll-like receptor 4 (TLR4) is a central regulator of innate immunity that primarily recognizes bacterial lipopolysaccharide cell wall constituents to trigger cytokine secretion. We identify the intramembrane protease RHBDL4 as a negative regulator of TLR4 signaling. We show that RHBDL4 triggers degradation of TLR4's trafficking factor TMED7. This counteracts TLR4 transport to the cell surface. Notably, TLR4 activation mediates transcriptional upregulation of RHBDL4 thereby inducing a negative feedback loop to reduce TLR4 trafficking to the plasma membrane. This secretory cargo tuning mechanism prevents the over-activation of TLR4-dependent signaling in an in vitro Mycobacterium tuberculosis macrophage infection model and consequently alleviates septic shock in a mouse model. A hypomorphic RHBDL4 mutation linked to Kawasaki syndrome, an ill-defined inflammatory disorder in children, further supports the pathophysiological relevance of our findings. In this work, we identify an RHBDL4-mediated axis that acts as a rheostat to prevent over-activation of the TLR4 pathway.

The Taussig-Bing anomaly: long-term results.

OBJECTIVES: The arterial switch operation (ASO) is the method of choice for the Taussig-Bing heart. The aim of the study was to analyse the long-term outcome of correction of the Taussig-Bing heart. METHODS: Between 1986 and 2011, 44 infants, including 18 newborns, underwent an ASO. The staged and the primary approach were used in 9 and 35 patients, respectively. Aortic arch (AA) obstruction (n = 26) and right ventricle outflow tract obstruction (n = 34) were common. The mean age at corrective surgery was 112.9 days; the mean weight was 4.17 kg. RESULTS: There were 1 early and 4 late deaths. Overall survival was 88% at 15 years, with a mean follow-up of 9.2 years. Freedom from reoperation was 67% at 15 years of follow-up. Eight and 6 patients required right and left ventricular outflow tract surgery, respectively, including resection of the right ventricular outflow tract obstruction (n = 8), a transanular patch (n = 6), aortic valve reconstruction (n = 3), aortic valve replacement (n = 2) and AA reoperation (n = 4). Freedom from aortic regurgitation >mild or aortic valve replacement/reconstruction was 76% at 15 years of follow-up. Freedom from any event was 56% at 15 years of follow-up. All patients are in sinus rhythm, and biventricular function is well-preserved in 95% of patients. All patients are doing well; 86% of them are without medication. CONCLUSIONS: Corrective surgery offers excellent survival benefits and encouraging long-term functional outcomes, regardless of the coronary anatomy and associated lesions. Normal biventricular function is preserved in the vast majority of patients, and >3/4 of patients are without cardiac medication. Nevertheless, TBH associated with a complex anatomy continues to be a risk factor for long-term morbidity, and redos and reinterventions are equally common on both outflow tracts. Progressive neoaortic regurgitation and neoaortic root dilatation might be a problem in the future; therefore, close lifelong surveillance of patients is necessary.