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    ON THE COVER
    Silva et al. describe a population of vasculature-associated fat macrophages that adapt to inflammatory and metabolic challenges. The cover shows a confocal image of epididymal full-mount sections showing the distribution of VAMs (dextran-rhodamine+DAPI+) in close contact to blood vessels labeled with isolectin. Bodipy labels lipid droplets in macrophages and adipocytes. The image was taken from the original manuscript and modified by the JEM editorial office. See page 786.

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ISSN 0022-1007
EISSN 1540-9538
In this Issue

Insights

In this issue of JEM, Reinink et al. use comparative lipidomics to identify a new family of trehalose-containing cell wall lipids that are enriched in virulent Salmonella serovars. These lipids are structurally related to the important mycobacterial immunogen cord factor.

A novel mouse model of liver cancer induced by iron overload through deleting the iron-sensing ubiquitin ligase FBXL5.

The epigenetic regulator EZH2 has opposing roles during initiation and maintenance of acute myeloid leukemia.

Brief Definitive Reports

ILCs are critical regulators of intestinal immune homeostasis and interactions with commensal bacteria. Melo-Gonzalez et al. show that ILC3 localize at the T–B cell interface of the colon-draining lymph node and interact with T follicular helper cells to limit mucosal IgA responses against commensal and pathogenic bacteria.

Zhu et al. show that SARM1 deficiency selectively up-regulates XAF1 expression, which, in turn, promotes prion-induced neuronal death and accelerates prion progression. This study reveals a novel link between SARM1, XAF1, and associated neuronal apoptosis in prion disease.

Articles

This work describes the discovery, biosynthesis, and chemical synthesis of a previously unknown class of lipids, trehalose phospholipids, in pathogenic Salmonella species. Trehalose phospholipids stimulate the innate immune receptor Mincle, the receptor for the strong adjuvant mycobacterial cord factor.

Optimal activation of IRF3 is crucial for maintaining immune homeostasis. Huai et al. demonstrate that KAT8 acetylates IRF3 at lysine 359, inhibits IRF3 recruitment to promoters of type I interferon genes, and then decreases type I interferon production to attenuate antiviral innate immune responses.

Silva et al. describe and characterize a population of adipose tissue macrophages (VAMs) that are in close contact with the vasculature and powerfully uptake blood-borne macromolecules. VAMs harbor a repair/detoxifying gene signature and adapt quickly to infections and fasting.

The intramembrane proteases SPPL2a/b control pro-atherogenic signaling of membrane-bound proteolytic fragments derived from the oxLDL receptor LOX-1. In mice deficient for these proteases, plaque development and fibrosis is enhanced. This highlights SPPL2a/b as crucial players of a novel athero-protective mechanism, which is conserved in humans.

Kimura et al. show that Sox8 is specifically expressed in intestinal M cells. Genetic deletion of Sox8 causes the loss of mature M cells and reduction of antigen uptake in Peyer’s patches, resulting in a decreased antigen-specific IgA response during the mouse juvenile period.

Tcf1 and Lef1 are underexpressed in T reg cells compared with conventional CD4+ T cells. Xing et al. demonstrate that genetic ablation of both factors impairs immunosuppressive function of T reg cells and leads to spontaneous multi-organ autoimmunity.

Wu et al. show that STING gain-of-function disease mutant disrupts calcium homeostasis and chronically activates ER stress as well as the unfolded protein response (UPR) through a newly identified “UPR motif,” leading to T cell death and lung disease.

Qian et al. shows that ILC2s can be generated from not only thymic multipotent progenitors but also committed T cell precursors. These processes are greatly suppressed by E protein transcription factors. Thymic ILC2s show functional differences from those made elsewhere.

Arnold et al. demonstrate critical roles for both integrin αVβ8 and TGFβ in the maturation of microglia and characterize the effects that microglia deficient in TGFβ signaling have on brain development.

This study demonstrates that astrocytic connexin43 gap junction hemichannels are largely controlled by four C-terminal tail–located serine residues and provides mechanistic insight on how phosphorylation of these residues affects recovery from stroke.

Diabetic nephropathy is a leading cause of kidney failure. VE-PTP phosphatase expression is increased in the endothelium of rodents with diabetes and hypertension. Genetic deletion of VE-PTP reduces kidney injury in diabetic mice, suggesting it may be a therapeutic target.

Hepatocellular iron overload elicited by ablation of the iron-sensing ubiquitin ligase FBXL5 promotes liver carcinogenesis induced by exposure to a chemical carcinogen or hepatitis virus, suggesting that FBXL5 is a previously unrecognized oncosuppressor in liver carcinogenesis in mice.

Basheer et al. show that EZH2 has stage-specific and diametrically opposite roles during the induction and maintenance stages of AML. However, different transcriptional programs are affected at each stage, identifying mutant EZH2 as a prognostic marker and paradoxically WT EZH2 as a potential therapeutic target.

Therapeutic resistance to PD-L1 blockade therapy following an initial positive response is increasingly observed. Gong et al. show that secreted PD-L1 splicing variants act as “decoys,” mediating resistance to the PD-L1 blockade therapy.

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