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Sox8 is essential for M cell maturation to accelerate IgA response at the early stage after weaning in mice
Microfold (M) cells residing in the follicle-associated epithelium (FAE) of the gut-associated lymphoid tissue are specialized for antigen uptake to initiate mucosal immune responses. The molecular machinery and biological significance of M cell differentiation, however, remain to be fully elucidated. Here, we demonstrate that Sox8, a member of the SRY-related HMG box transcription factor family, is specifically expressed by M cells in the intestinal epithelium. The expression of Sox8 requires activation of RANKL-RelB signaling. Chromatin immunoprecipitation and luciferase assays revealed that Sox8 directly binds the promo...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Kimura, S., Kobayashi, N., Nakamura, Y., Kanaya, T., Takahashi, D., Fujiki, R., Mutoh, M., Obata, Y., Iwanaga, T., Nakagawa, T., Kato, N., Sato, S., Kaisho, T., Ohno, H., Hase, K. Tags: Mucosal Immunology Articles Source Type: research

Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis
The lectin-like oxidized LDL receptor 1 (LOX-1) is a key player in the development of atherosclerosis. LOX-1 promotes endothelial activation and dysfunction by mediating uptake of oxidized LDL and inducing pro-atherogenic signaling. However, little is known about modulators of LOX-1–mediated responses. Here, we show that the function of LOX-1 is controlled proteolytically. Ectodomain shedding by the metalloprotease ADAM10 and lysosomal degradation generate membrane-bound N-terminal fragments (NTFs), which we identified as novel substrates of the intramembrane proteases signal peptide peptidase–like 2a and b (SP...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Mentrup, T., Theodorou, K., Cabrera-Cabrera, F., Helbig, A. O., Happ, K., Gijbels, M., Gradtke, A.-C., Rabe, B., Fukumori, A., Steiner, H., Tholey, A., Fluhrer, R., Donners, M., Schröder, B. Tags: Cardiovascular Biology Articles Source Type: research

Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges
Tissue-resident macrophages are the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophages (ATMs) change during metabolic stress and are thought to contribute to metabolic syndrome. Here, we studied ATM subpopulations in steady state and in response to nutritional and infectious challenges. We found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying very high endocytic capacity. We refer to these cells as vasculature-associated ATMs (VAMs). Chronic high-fat diet (HFD) results in the accumulation of a monoc...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Silva, H. M., Bafica, A., Rodrigues-Luiz, G. F., Chi, J., Santos, P. d. A., Reis, B. S., Hoytema van Konijnenburg, D. P., Crane, A., Arifa, R. D. N., Martin, P., Mendes, D. A. G. B., Mansur, D. S., Torres, V. J., Cadwell, K., Cohen, P., Mucida, D., Lafail Tags: Innate Immunity and Inflammation, Metabolism Articles Source Type: research

KAT8 selectively inhibits antiviral immunity by acetylating IRF3
The transcription factor interferon regulatory factor 3 (IRF3) is essential for virus infection–triggered induction of type I interferons (IFN-I) and innate immune responses. IRF3 activity is tightly regulated by conventional posttranslational modifications (PTMs) such as phosphorylation and ubiquitination. Here, we identify an unconventional PTM of IRF3 that directly inhibits its transcriptional activity and attenuates antiviral immune response. We performed an RNA interference screen and found that lysine acetyltransferase 8 (KAT8), which is ubiquitously expressed in immune cells (particularly in macrophages), sele...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Huai, W., Liu, X., Wang, C., Zhang, Y., Chen, X., Chen, X., Xu, S., Thomas, T., Li, N., Cao, X. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Articles Source Type: research

Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria
Salmonella species are among the world’s most prevalent pathogens. Because the cell wall interfaces with the host, we designed a lipidomics approach to reveal pathogen-specific cell wall compounds. Among the molecules differentially expressed between Salmonella Paratyphi and S. Typhi, we focused on lipids that are enriched in S. Typhi, because it causes typhoid fever. We discovered a previously unknown family of trehalose phospholipids, 6,6'-diphosphatidyltrehalose (diPT) and 6-phosphatidyltrehalose (PT). Cardiolipin synthase B (ClsB) is essential for PT and diPT but not for cardiolipin biosynthesis. Chemotyping outp...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Reinink, P., Buter, J., Mishra, V. K., Ishikawa, E., Cheng, T.-Y., Willemsen, P. T. J., Porwollik, S., Brennan, P. J., Heinz, E., Mayfield, J. A., Dougan, G., van Els, C. A., Cerundolo, V., Napolitani, G., Yamasaki, S., Minnaard, A. J., McClelland, M., Mo Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Articles Source Type: research

SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease
SARM1 (sterile α and HEAT/armadillo motif–containing protein) is a member of the MyD88 (myeloid differentiation primary response gene 88) family, which mediates innate immune responses. Because inactivation of SARM1 prevents various forms of axonal degeneration, we tested whether it might protect against prion-induced neurotoxicity. Instead, we found that SARM1 deficiency exacerbates the progression of prion pathogenesis. This deleterious effect was not due to SARM1-dependent modulation of prion-induced neuroinflammation, since microglial activation, astrogliosis, and brain cytokine profiles were not altered by...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Zhu, C., Li, B., Frontzek, K., Liu, Y., Aguzzi, A. Tags: Neuroinflammation, Neuroscience Brief Definitive Reports Source Type: research

Antigen-presenting ILC3 regulate T cell-dependent IgA responses to colonic mucosal bacteria
Intestinal immune homeostasis is dependent upon tightly regulated and dynamic host interactions with the commensal microbiota. Immunoglobulin A (IgA) produced by mucosal B cells dictates the composition of commensal bacteria residing within the intestine. While emerging evidence suggests the majority of IgA is produced innately and may be polyreactive, mucosal-dwelling species can also elicit IgA via T cell–dependent mechanisms. However, the mechanisms that modulate the magnitude and quality of T cell–dependent IgA responses remain incompletely understood. Here we demonstrate that group 3 innate lymphoid cells ...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Melo-Gonzalez, F., Kammoun, H., Evren, E., Dutton, E. E., Papadopoulou, M., Bradford, B. M., Tanes, C., Fardus-Reid, F., Swann, J. R., Bittinger, K., Mabbott, N. A., Vallance, B. A., Willinger, T., Withers, D. R., Hepworth, M. R. Tags: Mucosal Immunology Brief Definitive Reports Source Type: research

Dual roles of EZH2 in acute myeloid leukemia
In this issue of JEM, Basheer et al. (https://doi.org/10.1084/jem.20181276) describe opposing roles of the epigenetic regulator Ezh2 during initiation and maintenance of acute myeloid leukemia (AML). Ezh2 was found to have tumor suppressive and oncogenic functions in different phases of the same malignancy. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Skoda, R. C., Schwaller, J. Tags: Leukemia & Lymphoma Insights Source Type: research

Iron overload and liver cancer
In this issue of JEM, Muto et al. (https://doi.org/10.1084/jem.20180900) generate a novel mouse model of liver cancer induced by iron overload by deleting the iron-sensing ubiquitin ligase FBXL5 specifically in hepatocytes and exposure to a chemical carcinogen. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Molina-Sanchez, P., Lujambio, A. Tags: Solid Tumors, Tumor Immunology Insights Source Type: research

"Salmonella, meet mycobacteria."
In this issue of JEM, Reinink et al. (https://doi.org/10.1084/jem.20181812) 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. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Lovell-Read, S. R., de Carvalho, L. P. S. Tags: Insights Source Type: research

Human colon organoids reveal distinct physiologic and oncogenic Wnt responses
Constitutive Wnt activation upon loss of Adenoma polyposis coli (APC) acts as main driver of colorectal cancer (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiological Wnt activity, we have performed transcriptome and proteome profiling in isogenic human colon organoids. Culture in the presence or absence of exogenous ligand allowed us to discriminate receptor-mediated signaling from the effects of CRISPR/Cas9-induced APC loss. We could catalog two nonoverlapping molecular signatures that were stable at distinct lev...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Michels, B. E., Mosa, M. H., Grebbin, B. M., Yepes, D., Darvishi, T., Hausmann, J., Urlaub, H., Zeuzem, S., Kvasnicka, H. M., Oellerich, T., Farin, H. F. Tags: Solid Tumors, Stem Cells & Regeneration, Human Disease Genetics Articles Source Type: research

Heterotypic CAF-tumor spheroids promote early peritoneal metastatis of ovarian cancer
High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5high (ITGA5high) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination. Intriguingly, fibroblasts inside MUs support ATC survival and guide their peritoneal invasion before ...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Gao, Q., Yang, Z., Xu, S., Li, X., Yang, X., Jin, P., Liu, Y., Zhou, X., Zhang, T., Gong, C., Wei, X., Liu, D., Sun, C., Chen, G., Hu, J., Meng, L., Zhou, J., Sawada, K., Fruscio, R., Grunt, T. W., Wischhusen, J., Vargas-Hernandez, V. M., Pothuri, B., Col Tags: Solid Tumors Articles Source Type: research

Generation of pulmonary neuroendocrine cells and SCLC-like tumors from human embryonic stem cells
Cancer models based on cells derived from human embryonic stem cells (hESCs) may reveal why certain constellations of genetic changes drive carcinogenesis in specialized lineages. Here we demonstrate that inhibition of NOTCH signaling induces up to 10% of lung progenitor cells to form pulmonary neuroendocrine cells (PNECs), putative precursors to small cell lung cancers (SCLCs), and we can increase PNECs by reducing levels of retinoblastoma (RB) proteins with inhibitory RNA. Reducing levels of TP53 protein or expressing mutant KRAS or EGFR genes did not induce or expand PNECs, but tumors resembling early-stage SCLC grew in...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Chen, H. J., Poran, A., Unni, A. M., Huang, S. X., Elemento, O., Snoeck, H.-W., Varmus, H. Tags: Solid Tumors Articles Source Type: research

Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells. Mechanistically, EHF deficiency induced the conversion and expansion o...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Liu, J., Jiang, W., Zhao, K., Wang, H., Zhou, T., Bai, W., Wang, X., Zhao, T., Huang, C., Gao, S., Qin, T., Yu, W., Yang, B., Li, X., Fu, D., Tan, W., Yang, S., Ren, H., Hao, J. Tags: Solid Tumors, Tumor Immunology Articles Source Type: research

The transcription factor Duxbl mediates elimination of pre-T cells that fail {beta}-selection
T cell development is critically dependent on successful rearrangement of antigen-receptor chains. At the β-selection checkpoint, only cells with a functional rearrangement continue in development. However, how nonselected T cells proceed in their dead-end fate is not clear. We identified low CD27 expression to mark pre-T cells that have failed to rearrange their β-chain. Expression profiling and single-cell transcriptome clustering identified a developmental trajectory through β-selection and revealed specific expression of the transcription factor Duxbl at a stage of high recombination activity before &bet...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Klein, F., Mitrovic, M., Roux, J., Engdahl, C., von Muenchow, L., Alberti-Servera, L., Fehling, H. J., Pelczar, P., Rolink, A., Tsapogas, P. Tags: Articles Source Type: research