Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice.

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr-/- mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68+ and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68+ upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype.

Distribution of the putative type VI secretion system core genes in Klebsiella spp.

The type VI secretion system (t6ss) is a recently characterized secretion system which appears to be involved in bacterial pathogenesis as a potential nano-syringe for the translocation of effector proteins into the eukaryotic host cell cytoplasm. Until now no evidence was provided for the presence of t6ss in the genomes of the sequenced representatives of Klebsiella spp., including the human opportunistic pathogen Klebsiella pneumoniae. However, in a previous study by Lawlor et al. (2005), were revealed two insertion mutants in hypothetical proteins of K. pneumoniae with decreased ability to infect mouse spleen. Interestingly, these two putative proteins appear to be homologues with two characterized t6ss core proteins of Yersinia pestis. In order to investigate the presence of genes encoding for putative t6ss core components and putative effectors in Klebsiella spp., we have undertaken an in silico genome mining in three fully and one partially sequenced strains of K. pneumoniae, as well as a strain of the Klebsiella variicola. Moreover, we have investigated the phylogenetic relatedness of three core proteins of the Klebsiella t6ss with their orthologues of various bacteria species. Our analysis evidenced three distinguishable, conserved syntenies in Klebsiella spp. genomes that contain the recognised as putative t6ss genes. The results of our work taken together with the results on the functional analysis of insertion mutants, strongly suggest the existence of an organised t6ss mechanism that likely accounts of the host-pathogen interaction.