Type II NKT Cells Stimulate Diet-Induced Obesity by Mediating Adipose Tissue Inflammation, Steatohepatitis and Insulin Resistance

The progression of obesity is accompanied by a chronic inflammatory process that involves both innate and acquired immunity. Natural killer T (NKT) cells recognize lipid antigens and are also distributed in adipose tissue. To examine the involvement of NKT cells in the development of obesity, C57BL/6 mice (wild type; WT), and two NKT-cell-deficient strains, Jα18−/− mice that lack the type I subset and CD1d−/− mice that lack both the type I and II subsets, were fed a high fat diet (HFD). CD1d−/− mice gained the least body weight with the least weight in perigonadal and brown adipose tissue as well as in the liver, compared to WT or Jα18−/− mice fed an HFD. Histologically, CD1d−/− mice had significantly smaller adipocytes and developed significantly milder hepatosteatosis than WT or Jα18−/− mice. The number of NK1.1+TCRβ+ cells in adipose tissue increased when WT mice were fed an HFD and were mostly invariant Vα14Jα18-negative. CD11b+ macrophages (Mφ) were another major subset of cells in adipose tissue infiltrates, and they were divided into F4/80high and F4/80low cells. The F4/80low-Mφ subset in adipose tissue was increased in CD1d−/− mice, and this population likely played an anti-inflammatory role. Glucose intolerance and insulin resistance in CD1d−/− mice were not aggravated as in WT or Jα18−/− mice fed an HFD, likely due to a lower grade of inflammation and adiposity. Collectively, our findings provide evidence that type II NKT cells initiate inflammation in the liver and adipose tissue and exacerbate the course of obesity that leads to insulin resistance

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

The role of tumor necrosis factor-α for interleukin-10 production by murine dendritic cells

In the present study, we examined the role of tumor necrosis factor (TNF) in interleukin (IL)-10 production by dendritic cells (DCs) using bone-marrow derived DCs from wild type (WT) and TNF-α knockout (TNF-α^[-/-]) mice. Toll-like receptor (TLR) stimulation induced substantial level of IL-10 production by WT DCs, but significantly low level of IL-10 production by TNF-α^[-/-] DCs. In contrast, no significant difference was detected in IL-12 p40 production between WT and TNF-α^[-/-] DCs. Addition of TNF-α during TLR stimulation recovered the impaired ability of TNF-α^[-/-] DCs for IL-10 production. This recovery appeared to be associated with an activation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/Akt following the TNF-α addition. Blocking these kinases significantly inhibited IL-10 production by TNF-α^[-/-] DCs stimulated with TLR ligands plus TNF-α. Thus, TNF-α may be a key molecule to regulate the balance between anti-inflammatory versus inflammatory cytokine production in DCs

Dendritic cell-derived TNF-α is responsible for development of IL-10-producing CD4+ T cells

Immature dendritic cells (DCs) appear to be involved in peripheral immune tolerance via induction of IL-10-producing CD4+ T cells. We examined the role of TNF-α in generation of the IL-10-producing CD4+ T cells by immature DCs. Immature bone marrow-derived DCs from wild type (WT) or TNF-α^[-/-] mice were cocultured with CD4+ T cells from OVA specific TCR transgenic mice (OT-II) in the presence of OVA_[323-339] peptide. The WT DCs efficiently induced the antigen-specific IL-10-producing CD4+ T cells, while the ability of the TNF-α^[-/-] DCs to induce these CD4+ T cells was considerably depressed. Addition of exogenous TNF-α recovered the impaired ability of the TNF-α^[-/-] DCs to induce IL-10-producing T cells. However, no difference in this ability was observed between TNF-α^[-/-] and WT DCs after their maturation by LPS. Thus, TNF-α appears to be critical for the generation of IL-10-producing CD4+ T cells during the antigen presentation by immature DCs

Comparison of the relationship between multiple parameters of glycemic variability and coronary plaque vulnerability assessed by virtual histology-intravascular ultrasound

Aims/Introduction Increased glycemic variability is an important contributing factor to coronary artery disease. Although various parameters of glycemic variability can be derived by continuous glucose monitoring, the clinical relevance of individual parameters has remained unclear. We have now analyzed the relationship of such parameters to coronary plaque vulnerability. Materials and Methods The standard deviation of glucose levels (SD glucose), mean amplitude of glycemic excursions (MAGE), continuous overlapping net glycemic action calculated every 1 h (CONGA-1) and mean of daily differences (MODD) were calculated from continuous glucose monitoring data for 53 patients hospitalized for percutaneous coronary intervention. The relationship of these parameters to the percentage necrotic core of total plaque volume (%NC) as assessed by virtual histology-intravascular ultrasound (a predictor of coronary plaque rupture) was evaluated. Results All parameters of glycemic variability were significantly correlated with %NC, with correlation coefficients of 0.593, 0.626, 0.318, and 0.388 for log(SD glucose), log(MAGE), CONGA-1 and log(MODD), respectively. Simple linear regression analysis showed that the coefficients of determination for %NC and either log(SD glucose; 0.352) or log(MAGE; 0.392) were greater than those for %NC and either CONGA-1 (0.101) or log(MODD; 0.151), whereas the residual sums of squares for the former relationships (1045.1 and 979.5, respectively) were smaller than those for the latter (1449.3 and 1369.6, respectively). Conclusions The present data suggest that SD glucose and MAGE are more highly correlated with coronary plaque vulnerability than are CONGA-1 and MODD, and are thus likely better predictors of coronary artery disease