Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses.

As one of the most induced genes in activated macrophages, immune-responsive gene 1 (IRG1) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses.

Relationship of Physical Activity With Anxiety and Depression Symptoms in Chinese College Students During the COVID-19 Outbreak.

INTRODUCTION: During the COVID-19 outbreak, many citizens were asked to stay at home in self-quarantine, which can pose a significant challenge with respect to remaining physically active and maintaining mental health. This study aimed to evaluate the prevalence of inadequate physical activity, anxiety, and depression and to explore the relationship of physical activity with anxiety and depression symptoms among Chinese college students during quarantine. METHOD: Using a web-based cross-sectional survey, we collected data from 1,396 Chinese college students. Anxiety and depression were assessed with the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS), respectively. The data on physical activity were collected by types of physical activity and the International Physical Activity Questionnaire (IPAQ-SF). RESULTS: During the COVID-19 outbreak, about 52.3% of Chinese college students had inadequate physical activity. The rates of anxiety and depression symptoms were 31.0 and 41.8%, respectively. A high level of physical activity (ß = -0.121, P < 0.001) was significantly closely associated with low anxiety, while a moderate (ß = -0.095, P = 0.001), or high (ß = -0.179, P < 0.001) level of physical activity was significantly closely associated with reduced depression after adjusting confounding demographic factors. Moreover, specific types of physical activity, such as stretching and resistance training, were negatively correlated with both anxiety and depression; doing household chores was negatively correlated with depression. CONCLUSION: Our findings highlight specific levels and types of home-based physical activities that need to be taken into consideration to protect the mental health of college students during the COVID-19 epidemic.

Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy.

Loss-of-function mutations in genes encoding TET DNA dioxygenase occur frequently in hematopoietic malignancy, but rarely in solid tumors which instead commonly have reduced activity. The impact of decreased TET activity in solid tumors is not known. Here we show that TET2 mediates interferon γ (IFNγ)-JAK-STAT signaling pathway to control chemokine and PD-L1 expression, lymphocyte infiltration and cancer immunity. IFNγ stimulated STAT1 to bind TET2 and recruit TET2 to hydroxymethylate chemokine and PD-L1 genes. Reduced TET activity was associated with decreased TH1-type chemokines and tumor-infiltrating lymphocytes (TILs) and the progression of human colon cancer. Deletion of Tet2 in murine melanoma and colon tumor cells reduced chemokine expression and TILs, enabling tumors to evade anti-tumor immunity and to resist anti-PD-L1 therapy. Conversely, stimulating TET activity by systematic injection of its co-factor, ascorbate/vitamin C, increased chemokine and TILs, leading to enhanced anti-tumor immunity and anti-PD-L1 efficacy and extended lifespan of tumor-bearing mice. These results suggest an IFNγ-JAK-STAT-TET signaling pathway that mediates tumor response to anti-PD-L1/PD-1 therapy and is frequently disrupted in solid tumors. Our findings also suggest TET activity as a biomarker for predicting the efficacy and patient response to anti-PD-1/PD-L1 therapy, and stimulating TET activity as an adjuvant immunotherapy of solid tumors.