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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“Salmonella, meet mycobacteria.”
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.
Iron overload and liver cancer
A novel mouse model of liver cancer induced by iron overload through deleting the iron-sensing ubiquitin ligase FBXL5.
Dual roles of EZH2 in acute myeloid leukemia
The epigenetic regulator EZH2 has opposing roles during initiation and maintenance of acute myeloid leukemia.
Brief Definitive Reports
Antigen-presenting ILC3 regulate T cell–dependent IgA responses to colonic mucosal bacteria
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.
SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease
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.
Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria
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.
KAT8 selectively inhibits antiviral immunity by acetylating IRF3
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.
Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges
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.
Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis
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.
Sox8 is essential for M cell maturation to accelerate IgA response at the early stage after weaning in mice
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 required for the immunosuppressive function of regulatory T cells
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.
STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death
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.
Suppression of ILC2 differentiation from committed T cell precursors by E protein transcription factors
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.
Impaired αVβ8 and TGFβ signaling lead to microglial dysmaturation and neuromotor dysfunction
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.
Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke
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.
Targeting VE-PTP phosphatase protects the kidney from diabetic injury
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.
Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis
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.
Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML
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.
Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non–small cell lung cancer
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.