The immune-response gene 1 (IRG1) plays a key role in anti-pathogen defense, as deletion of Irg1 in mice causes severe defects in response to bacterial and viral infection, and decreased survival 1, 2 . IRG1 transcription is rapidly induced by pathogen infection and in ammatory conditions primarily in cells of myeloid lineage 3 . IRG1 encodes a mitochondrial metabolic enzyme, aconitate decarboxylase 1 (ACOD1), that catalyzes the decarboxylation of cis-aconitate to produce the anti-in ammatory metabolite itaconic acid (ITA) 4 . Several molecular processes are affected by ITA, including succinate dehydrogenase (SDH) inhibition 5 , resulting in succinate accumulation and metabolic reprogramming 6,7 , and alkylation of protein cysteine residues, inducing the electrophilic stress response mediated by NRF2 and IκBζ 8, 9 and impairing aerobic glycolysis 10 . However, the mechanisms by which ITA exerts its profound antiin ammatory effect still remains to be fully elucidated. Here, we show that ITA is a potent inhibitor of the TET family DNA dioxygenases, which catalyze the conversion of 5-methylcytosine (5mC) to 5hydroxymethylcytosine (5hmC) during the process of active DNA demethylation. ITA binds to the same site of α-ketoglutarate (α-KG) in TET2, inhibiting its catalytic activity. Lipopolysaccharides (LPS) treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals TET2 is a major target of ITA in suppressing LPS-induced genes, including those regulated by NF-κB and STAT signaling pathways. In vivo, ITA decreases 5hmC, reduces LPS-induced acute pulmonary edema and lung and liver injury, and protects mice against lethal endotoxaemia in a manner that is dependent on the catalytic activity of Tet2. Our study thus identi es ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the in ammatory response. MainDeletion of the Irg1 gene or treatment with cell permeable ITA alters the transcriptional signature in response to LPS 2 . We speculated that ITA may impact epigenetics to in uence gene expression, and therefore, we determined the effect of Irg1 expression and ITA accumulation on global histone and DNA de/methylation in transfected HEK293T cells (Extended Data Fig. 1a). We found that ectopic expression of either wild-type or catalytic inactive mutant Irg1 had little effect on mono-, di-, and trimethylation of all ve histone H3 lysine residues (Extended Data Fig. 1b, 1c). In contrast, expression of wild-type Irg1, but not the catalytic inactive mutant, dramatically reduced Tet2-mediated global 5hmC in cells (Fig. 1a and Extended Data Fig. 1d-e). Like α-KG, which is a crucial co-substrate for the activity of TET2, ITA is also a dicarboxylic acid containing a 4-or 5-carboxylate that, in the case of α-KG, forms hydrogen and ionic bonds with H1416, R1896, and S1898 in TET2 11 . Of note, α-KG binds to Fe(II) in a bidentate manner via its C-1 carboxylate and C-2 keto groups, which are lacking in ITA. This raises the possibi...

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak began in December 2019, causing the illness known as the novel coronavirus disease 2019 (COVID-19). The virus spread rapidly worldwide to become a global public health emergency. As of 15 November 2020, more than 53 million confirmed cases and over one million deaths worldwide have been reported (World Health Organization, 2020). The SARS-CoV-2 genome was sequenced and studies are ongoing to further understand the epidemiology, clinical manifestations, etiological structure, cellular receptor angiotensin II converting enzyme (ACE2), and intracellular replication process of the virus. Currently, thousands of clinical trials related to SARS-CoV-2 are underway (https://clinicaltrials.gov/). However, no vaccines or drugs have yet been approved, until very recently, for direct treatment or prevention of COVID-19 and only supportive treatment has been applied clinically. This review will discuss the possible mechanism of the innate immune response to SARS-CoV-2 infection and provide insight into the development of related therapeutics.

Large numbers of people in many countries report being lonely with rates highest among the very old. Does the built environment affect loneliness among older people and if so, how? Using a scoping review, we examined associations between loneliness and built environments at the block, neighborhood, and city scales. The (1) neighborhood environment has received most attention. Research has also examined (2) urban contexts, (3) housing, and (4) transportation access. Findings are mixed with the stronger evidence that local resources, walkability, overall environment quality, housing options, and nearby transportation alternatives can help combat loneliness.