Macrophage RAGE activation is proinflammatory in NASH.

Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte-derived macrophages. The receptor for advanced glycation endproducts (RAGE) is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that RAGE-expressing macrophages are proinflammatory and mediate liver inflammation in NASH. Compared with healthy controls, RAGE expression was increased in liver biopsies from patients with NASH. In a high-fat, -fructose, and -cholesterol-induced (FFC)-induced murine model of NASH, RAGE expression was increased, specifically on recruited macrophages. FFC mice that received a pharmacological inhibitor of RAGE (TTP488), and myeloid-specific RAGE KO mice (RAGE-MKO) had attenuated liver injury associated with a reduced accumulation of RAGE+ recruited macrophages. Transcriptomics analysis suggested that pathways of macrophage and T cell activation were upregulated by FFC diet, inhibited by TTP488 treatment, and reduced in RAGE-MKO mice. Correspondingly, the secretome of ligand-stimulated BM-derived macrophages from RAGE-MKO mice had an attenuated capacity to activate CD8+ T cells. Our data implicate RAGE as what we propose to be a novel and potentially targetable mediator of the proinflammatory signaling of recruited macrophages in NASH.

Interleukin-21 Drives a Hypermetabolic State and CD4+ T Cell-associated Pathogenicity in Chronic Intestinal Inflammation.

BACKGROUND & AIMS: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease (IBD); however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODS: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing Seahorse XF analyzer. We utilized Crohn's disease single-cell RNA sequencing dataset to infer therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically-modified Tregs in CD4+ T cell-induced murine colitis models. RESULTS: Mitochondria-endoplasmic reticulum (ER) appositions, known to mediate pyruvate entry into mitochondria via VDAC1, are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate (MePyr) supplementation. Notably, IL-21 diminished mitochondria-ER appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 ß (GSK3ß), a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. MePyr and GSK3ß pharmacologic inhibitor (LY2090314) reversed IL-21-induced metabolic rewiring and inflammatory state. Moreover, IL-21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONS: IL-21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL-21-induced metabolism in Tregs may mitigate CD4+ T cell-driven chronic intestinal inflammation.

Recurrence of a Unicameral Bone Cyst in the Femoral Diaphysis

Diaphyseal unicameral bone cysts of the long bone are generally known to originate near the growth plate and migrate from the metaphysis to the diaphysis during skeletal growth. In the case of unicameral bone cysts of diaphyseal origin, recurrence at the same location is extremely rare. We report a case of recurrence of a unicameral bone cyst in the diaphysis of the femur that developed 8 years after treatment with curettage and bone grafting. We performed bone grafting and lengthening of the affected femur with an application of the Ilizarov apparatus over an intramedullary nail to treat the cystic lesion and limb length discrepancy simultaneously.

A Multi-center Study for Birth Defect Monitoring Systems in Korea

The aim of this study was to establish a multi-center birth defects monitoring system to evaluate the prevalence and the serial occurrence of birth defects in Korea. Ten medical centers participated in this program. A trained nurse collected relevant records from delivery units and pediatric clinics in participating hospitals on a monthly basis. We observed 1,537 cases of birth defects among 86,622 deliveries, which included live births and stillbirths. The prevalence of birth defects was 1.8%, and the sex distribution of the birth defect cases was 55.2% male and 41.6% female. The highest proportion of birth defects was in the cardiovascular system (17.5%), followed by birth defects involving in the genitourinary system (15.6%). Chromosomal anomalies were detected 30.0 per 10,000 births. Of these chromosomal anomalies, Down syndrome was most frequently observed. This study led to an establishment of a multi-center active monitoring system for birth defects. To better understand the serial occurrence of birth defects in Korea, it is necessary to increase the number of participating hospitals and to launch on a nation-wide multi-center study.