The helminth T2 RNase ω1 promotes metabolic homeostasis in an IL-33- and group 2 innate lymphoid cell-dependent mechanism.

Induction of a type 2 cellular response in the white adipose tissue leads to weight loss and improves glucose homeostasis in obese animals. Injection of obese mice with recombinant helminth-derived Schistosoma mansoni egg-derived ω1 (ω1), a potent inducer of type 2 activation, improves metabolic status involving a mechanism reliant upon release of the type 2 initiator cytokine IL-33. IL-33 initiates the accumulation of group 2 innate lymphoid cells (ILC2s), eosinophils, and alternatively activated macrophages in the adipose tissue. IL-33 release from cells in the adipose tissue is mediated by the RNase activity of ω1; however, the ability of ω1 to improve metabolic status is reliant upon effective binding of ω1 to CD206. We demonstrate a novel mechanism for RNase-mediated release of IL-33 inducing ILC2-dependent improvements in the metabolic status of obese animals.

Functions for Retinoic Acid-Related Orphan Receptor Alpha (RORα) in the Activation of Macrophages During Lipopolysaccharide-Induced Septic Shock.

The transcription factor Related Orphan Receptor Alpha (RORα) plays an important role in regulating circadian rhythm, inflammation, metabolism and cellular development. Herein we show that in the absence of functional RORα in mice there is reduced susceptibility to LPS-induced endotoxic shock, with selective decreases in release of pro-inflammatory cytokines. Treatment of mice with a RORα selective synthetic inhibitor also reduced the severity of LPS-induced endotoxemia. The reduction in responses in Rora deficient mice was associated with an alterations in metabolic and pro-inflammatory functions of macrophages, both in vivo peritoneal macrophages and in vitro generated bone marrow derived macrophages. Using LysMCreRorafl/sg mice the reduced susceptibility to LPS was shown to be specific to Rora expression in the macrophages. This study identifies that Rora-mediated regulation of macrophages impacts on the pro-inflammatory responses elicited by LPS.

Role for Retinoic Acid-Related Orphan Receptor Alpha (RORα) Expressing Macrophages in Diet-Induced Obesity.

The transcription factor RORα plays an important role in regulating circadian rhythm, inflammation, metabolism, and cellular development. Herein we show a role for RORα-expressing macrophages in the adipose tissue in altering the metabolic state of mice on a high-fat diet. The expression of Rora and RORA is elevated in white adipose tissue from obese mice and humans when compared to lean counterparts. When fed a high-fat diet Rora reporter mice revealed increased expression of Rora-YFP in macrophages in white adipose tissue deposits. To further define the potential role for Rora-expressing macrophages in the generation of an aberrant metabolic state Rorafl/flLysMCre/+ mice, which do not express Rora in myeloid cells, were maintained on a high-fat diet, and metabolic parameters assessed. These mice had significantly impaired weight gain and improved metabolic parameters in comparison to Rorafl/fl control mice. Further analysis of the immune cell populations within white adipose tissue deposits demonstrates a decrease in inflammatory adipose tissue macrophages (ATM). In obese reporter mouse there was increased in Rora-YFP expressing ATM in adipose tissue. Analysis of peritoneal macrophage populations demonstrates that within the peritoneal cavity Rora-expression is limited to myeloid-derived macrophages, suggesting a novel role for RORα in macrophage development and activation, which can impact on metabolism, and inflammation.

Macrophage and Innate Lymphoid Cell Interplay in the Genesis of Fibrosis.

Fibrosis is a characteristic pathological feature of an array of chronic diseases, where development of fibrosis in tissue can lead to marked alterations in the architecture of the affected organs. As a result of this process of sustained attrition to organs, many diseases that involve fibrosis are often progressive conditions and have a poor long-term prognosis. Inflammation is often a prelude to fibrosis, with innate and adaptive immunity involved in both the initiation and regulation of the fibrotic process. In this review, we will focus on the emerging roles of the newly described innate lymphoid cells (ILCs) in the generation of fibrotic disease with an examination of the potential interplay between ILC and macrophages and the adaptive immune system.

Effect of genetic variant in BICC1 on functional and structural brain changes in depression.

Genes and early-life adversity (ELA) interactively increase the risk of developing major depressive disorder (MDD). A recent genome-wide association study suggests that the minor T-allele of single-nucleotide polymorphisms in the bicaudal C homolog 1 gene (BICC1) has a protective role against MDD. The aims of the study were to investigate whether the minor T-allele of BICC1 is protective against hippocampal structural brain changes, whether it is associated with increased functional brain activity in the emotion regulation system, and how ELA would modify this association. Forty-four patients with MDD and 44 healthy controls were investigated using structural magnetic resonance imaging (MRI) and functional MRI with an emotion inhibition task. Analysis of a single-nucleotide polymorphism in the BICC1-1 (rs999845) gene was performed. Right hippocampal bodies of patients and controls without a history of ELA and who carry the protective T-allele of BICC1 were significantly larger compared with those participants homozygous for the major C-allele of BICC1. However, MDD patients with ELA, who carry the T-allele, had smaller hippocampal head volumes compared with MDD patients without ELA. FMRI showed that patients and controls carrying the protective T-allele of BICC1 activate the emotion regulation system significantly more compared with those participants homozygous for the major C-allele (p<0.05, family wise error corrected). These results are suggestive that the minor T-allele of BICC1 has a protective role against MDD and its known structural and functional brain changes. However, this protective effect seems to be lost in the case of co-occurrence of ELA.