A lncRNA from an inflammatory bowel disease risk locus maintains intestinal host-commensal homeostasis.

Inflammatory bowel diseases (IBD) are known to have complex, genetically influenced etiologies, involving dysfunctional interactions between the intestinal immune system and the microbiome. Here, we characterized how the RNA transcript from an IBD-associated long non-coding RNA locus ("CARINH-Colitis Associated IRF1 antisense Regulator of Intestinal Homeostasis") protects against IBD. We show that CARINH and its neighboring gene coding for the transcription factor IRF1 together form a feedforward loop in host myeloid cells. The loop activation is sustained by microbial factors, and functions to maintain the intestinal host-commensal homeostasis via the induction of the anti-inflammatory factor IL-18BP and anti-microbial factors called guanylate-binding proteins (GBPs). Extending these mechanistic insights back to humans, we demonstrate that the function of the CARINH/IRF1 loop is conserved between mice and humans. Genetically, the T allele of rs2188962, the most probable causal variant of IBD within the CARINH locus from the human genetics study, impairs the inducible expression of the CARINH/IRF1 loop and thus increases genetic predisposition to IBD. Our study thus illustrates how an IBD-associated lncRNA maintains intestinal homeostasis and protects the host against colitis.

Supreme Catalytic Properties of Enzyme Nanoparticles Based on Ferritin Self-Assembly.

In this study, we aimed to address if enzymes self-assembled on the biological nanosphere matrix would have some nanoscale effects and then improve the catalytic ability and other characteristics especially for the resistance to adverse conditions. Initially, we evaluated two different forms of ferritins, DNA-binding protein from starved cells (Dps) and recombinant heavy chain of human ferritin (rHF), fused with methyl parathion hydrolase (MPH) to be self-assembled as the dodecamer and 24-mer enzyme nanoparticles (enzyme-NPs), Dps-MPH and MPH-rHF. Both self-assembled enzyme-NPs showed superior catalytic activity and kcat drastically increased, but MPH-rHF showed better performance than Dps-MPH. Next, Escherichia coli alkaline phosphatase (EAP) and the canonical mutant EAP(D101S) were chosen to confirm if rHF-based self-assembly generally improves the catalysis of enzymes with the different catalytic abilities. Additionally, restoration of the enzyme native forms on the rHF shell by increasing the flexibility of the polylinker between the catalytic units and the nanoscaffold further improved the catalytic activities of enzyme-NPs. Some of the nanoparticles exhibited better residual activities under extreme conditions. Conclusively, the enzyme-NPs based on rHF self-assembly provided an effective strategy for enzyme engineering.

FoxO1 is a regulator of MHC-II expression and anti-tumor effect of tumor-associated macrophages.

Macrophages are a critical component in host immune responses against tumor. In this work we investigated the role of forkhead box O1 (FoxO1) in the transcriptional regulation in macrophages, which affects the anti-tumor functions of tumor-associated macrophages (TAMs). First, we showed that TAMs expressed reduced levels of FoxO1, which was associated with their protumoral M2 polarization state. The suppression of FoxO1 expression in TAM was induced by the hypoxic condition in the tumor microenviroment. Next, we confirmed that FoxO1 positively regulates MHC-II genes by binding to the promoter region of Ciita gene, the master activator of multiple MHC-II genes. Loss of FoxO1 in TAMs resulted in reduced MHC-II expression. Furthermore, we used FoxO1 conditional knockout mice to show that FoxO1 deficiency in myeloid cells exacerbates tumor growth. These results demonstrate that the protumoral property of TAMs is induced by the hypoxia-triggered FoxO1 deficiency, which could be a potential target of novel anti-tumor therapies.