Correction: An essential role of high-molecular-weight kininogen in endotoxemia
Vol. 214, No. 9, September 4, 2017. 10.1084/jem.20161900 The authors regret that an error appeared in the original version of Fig. 3. In the upper panels of D, the image for Kng1+/+ mice was taken from the... (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Yang, A., Xie, Z., Wang, B., Colman, R. W., Dai, J., Wu, Y. Tags: Corrections Source Type: research

Hierarchical assembly and disassembly of a transcriptionally active RAG locus in CD4+CD8+ thymocytes
Expression of Rag1 and Rag2 is tightly regulated in developing T cells to mediate TCR gene assembly. Here we have investigated the molecular mechanisms governing the assembly and disassembly of a transcriptionally active RAG locus chromatin hub in CD4+CD8+ thymocytes. Rag1 and Rag2 gene expression in CD4+CD8+ thymocytes depends on Rag1 and Rag2 promoter activation by a distant antisilencer element (ASE). We identify GATA3 and E2A as critical regulators of the ASE, and Runx1 and E2A as critical regulators of the Rag1 promoter. We reveal hierarchical assembly of a transcriptionally active chromatin hub containing the ASE and...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Naik, A. K., Byrd, A. T., Lucander, A. C. K., Krangel, M. S. Tags: Hematopoiesis Articles Source Type: research

VEGF expands erythropoiesis via hypoxia-independent induction of erythropoietin in noncanonical perivascular stromal cells
Insufficient erythropoiesis due to increased demand is usually met by hypoxia-driven up-regulation of erythropoietin (Epo). Here, we uncovered vascular endothelial growth factor (VEGF) as a novel inducer of Epo capable of increasing circulating Epo under normoxic, nonanemic conditions in a previously unrecognized reservoir of Epo-producing cells (EPCs), leading to expansion of the erythroid progenitor pool and robust splenic erythropoiesis. Epo induction by VEGF occurs in kidney, liver, and spleen in a population of Gli1+SMA+PDGFRβ+ cells, a signature shared with vascular smooth muscle cells (VSMCs) derived from mesen...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Greenwald, A. C., Licht, T., Kumar, S., Oladipupo, S. S., Iyer, S., Grunewald, M., Keshet, E. Tags: Hematopoiesis Articles Source Type: research

IL-17R-EGFR axis links wound healing to tumorigenesis in Lrig1+ stem cells
This study demonstrates that IL-17A activates the IL-17R–EGFR axis in Lrig1+ stem cells linking wound healing to tumorigenesis. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Chen, X., Cai, G., Liu, C., Zhao, J., Gu, C., Wu, L., Hamilton, T. A., Zhang, C.-j., Ko, J., Zhu, L., Qin, J., Vidimos, A., Koyfman, S., Gastman, B. R., Jensen, K. B., Li, X. Tags: Solid Tumors, Stem Cells & Regeneration, Tumor Immunology Articles Source Type: research

Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum
Ovarian cancer preferentially metastasizes to the omentum, a fatty tissue characterized by immune structures called milky spots, but the cellular dynamics that direct this tropism are unknown. Here, we identified that neutrophil influx into the omentum is a prerequisite premetastatic step in orthotopic ovarian cancer models. Ovarian tumor–derived inflammatory factors stimulated neutrophils to mobilize and extrude chromatin webs called neutrophil extracellular traps (NETs). NETs were detected in the omentum of ovarian tumor–bearing mice before metastasis and of women with early-stage ovarian cancer. NETs, in tur...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Lee, W., Ko, S. Y., Mohamed, M. S., Kenny, H. A., Lengyel, E., Naora, H. Tags: Solid Tumors Articles Source Type: research

Cohesin-mediated NF-{kappa}B signaling limits hematopoietic stem cell self-renewal in aging and inflammation
This study shows that aged hematopoietic stem and progenitor cells (HSPCs) exhibit increased ground-stage NF-B activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-B signaling, which increases chromatin accessibility in the vicinity of NF-B target genes in response to inflammation. Rad21 is required for normal differentiation, but limits self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-B–dependent manner. HSCs from aged mice fail to down-regula...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Chen, Z., Amro, E. M., Becker, F., Hölzer, M., Rasa, S. M. M., Njeru, S. N., Han, B., Di Sanzo, S., Chen, Y., Tang, D., Tao, S., Haenold, R., Groth, M., Romanov, V. S., Kirkpatrick, J. M., Kraus, J. M., Kestler, H. A., Marz, M., Ori, A., Neri, F., Tags: Hematopoiesis Articles Source Type: research

A common transcriptomic program acquired in the thymus defines tissue residency of MAIT and NKT subsets
Mucosal-associated invariant T (MAIT) cells are abundant T cells with unique specificity for microbial metabolites. MAIT conservation along evolution indicates important functions, but their low frequency in mice has hampered their detailed characterization. Here, we performed the first transcriptomic analysis of murine MAIT cells. MAIT1 (RORtneg) and MAIT17 (RORt+) subsets were markedly distinct from mainstream T cells, but quasi-identical to NKT1 and NKT17 subsets. The expression of similar programs was further supported by strong correlations of MAIT and NKT frequencies in various organs. In both mice and humans, MAIT s...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Salou, M., Legoux, F., Gilet, J., Darbois, A., du Halgouet, A., Alonso, R., Richer, W., Goubet, A.-G., Daviaud, C., Menger, L., Procopio, E., Premel, V., Lantz, O. Tags: Articles Source Type: research

Viral MHCI inhibition evades tissue-resident memory T cell formation and responses
Tissue-resident memory CD8+ T cells (TRMs) confer rapid protection and immunity against viral infections. Many viruses have evolved mechanisms to inhibit MHCI presentation in order to evade CD8+ T cells, suggesting that these mechanisms may also apply to TRM-mediated protection. However, the effects of viral MHCI inhibition on the function and generation of TRMs is unclear. Herein, we demonstrate that viral MHCI inhibition reduces the abundance of CD4+ and CD8+ TRMs, but its effects on the local microenvironment compensate to promote antigen-specific CD8+ TRM formation. Unexpectedly, local cognate antigen enhances CD8+ TRM...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Lauron, E. J., Yang, L., Harvey, I. B., Sojka, D. K., Williams, G. D., Paley, M. A., Bern, M. D., Park, E., Victorino, F., Boon, A. C. M., Yokoyama, W. M. Tags: Infectious Disease and Host Defense Articles Source Type: research

Inducible down-regulation of MHC class I results in natural killer cell tolerance
Natural killer (NK) cells are innate lymphocytes that are thought to kill cells that down-regulate MHC class I (MHC-I) through "missing-self" recognition. NK cells from B2m–/– mice that lack surface MHC-I, however, are not autoreactive as predicted by the missing-self hypothesis. As a result, it is unclear if MHC-I down-regulation in vivo induces NK cell reactivity or tolerance to missing-self. Here, we generated a floxed B2m mouse to acutely down-regulate MHC-I in vivo in a host that normally expresses MHC-I. Global down-regulation of MHC-I induced NK cell hyporesponsiveness and tolerance to missing-self witho...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Bern, M. D., Parikh, B. A., Yang, L., Beckman, D. L., Poursine-Laurent, J., Yokoyama, W. M. Tags: Innate Immunity and Inflammation, Tolerance Articles Source Type: research

Inhibiting antibiotic-resistant Enterobacteriaceae by microbiota-mediated intracellular acidification
Klebsiella pneumoniae, Escherichia coli, and other members of the Enterobacteriaceae family are common human pathogens that have acquired broad antibiotic resistance, rendering infection by some strains virtually untreatable. Enterobacteriaceae are intestinal residents, but generally represent <1% of the adult colonic microbiota. Antibiotic-mediated destruction of the microbiota enables Enterobacteriaceae to expand to high densities in the colon, markedly increasing the risk of bloodstream invasion, sepsis, and death. Here, we demonstrate that an antibiotic-naive microbiota suppresses growth of antibiotic-resistant clin...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Sorbara, M. T., Dubin, K., Littmann, E. R., Moody, T. U., Fontana, E., Seok, R., Leiner, I. M., Taur, Y., Peled, J. U., van den Brink, M. R. M., Litvak, Y., Bäumler, A. J., Chaubard, J.-L., Pickard, A. J., Cross, J. R., Pamer, E. G. Tags: Infectious Disease and Host Defense Articles Source Type: research

Astrocytes and microglia: Models and tools
Glial cells serve as fundamental regulators of the central nervous system in development, homeostasis, and disease. Discoveries into the function of these cells have fueled excitement in glial research, with enthusiastic researchers addressing fundamental questions about glial biology and producing new scientific tools for the community. Here, we outline the pros and cons of in vivo and in vitro techniques to study astrocytes and microglia with the goal of helping researchers quickly identify the best approach for a given research question in the context of glial biology. It is truly a great time to be a glial biologist. (...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Guttenplan, K. A., Liddelow, S. A. Tags: Neuroinflammation, Neuroscience Review Source Type: research

Immune cells and CNS physiology: Microglia and beyond
Recent advances have directed our knowledge of the immune system from a narrative of "self" versus "nonself" to one in which immune function is critical for homeostasis of organs throughout the body. This is also the case with respect to the central nervous system (CNS). CNS immunity exists in a segregated state, with a marked partition occurring between the brain parenchyma and meningeal spaces. While the brain parenchyma is patrolled by perivascular macrophages and microglia, the meningeal spaces are supplied with a diverse immune repertoire. In this review, we posit that such partition allows for neuro–immune cros...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Norris, G. T., Kipnis, J. Tags: Neuroinflammation, Neuroscience Review Source Type: research

Microbiome-microglia connections via the gut-brain axis
Microglia, the resident immune cells in the brain, are essential for modulating neurogenesis, influencing synaptic remodeling, and regulating neuroinflammation by surveying the brain microenvironment. Microglial dysfunction has been implicated in the onset and progression of several neurodevelopmental and neurodegenerative diseases; however, the multitude of factors and signals influencing microglial activity have not been fully elucidated. Microglia not only respond to local signals within the brain but also receive input from the periphery, including the gastrointestinal (GI) tract. Recent preclinical findings suggest th...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Abdel-Haq, R., Schlachetzki, J. C. M., Glass, C. K., Mazmanian, S. K. Tags: Neuroinflammation Review Source Type: research

The gut microbiome: Relationships with disease and opportunities for therapy
Over the past decade, our view of human-associated microbes has expanded beyond that of a few species toward an appreciation of the diverse and niche-specialized microbial communities that develop in the human host with chronological age. The largest reservoir of microbes exists in the distal gastrointestinal tract, both in the lumen, where microbes facilitate primary and secondary metabolism, and on mucosal surfaces, where they interact with host immune cell populations. While local microbial-driven immunomodulation in the gut is well described, more recent studies have demonstrated a role for the gut microbiome in influe...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Durack, J., Lynch, S. V. Tags: Innate Immunity and Inflammation Review Source Type: research

Enlisting commensal microbes to resist antibiotic-resistant pathogens
The emergence of antibiotic-resistant bacterial pathogens is an all-too-common consequence of antibiotic use. Although antibiotic resistance among virulent bacterial pathogens is a growing concern, the highest levels of antibiotic resistance occur among less pathogenic but more common bacteria that are prevalent in healthcare settings. Patient-to-patient transmission of these antibiotic-resistant bacteria is a perpetual concern in hospitals. Many of these resistant microbes, such as vancomycin-resistant Enterococcus faecium and carbapenem-resistant Klebsiella pneumoniae, emerge from the intestinal lumen and invade the bloo...
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Keith, J. W., Pamer, E. G. Tags: Infectious Disease and Host Defense, Mucosal Immunology Review Source Type: research