The Journal of Experimental Medicine This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.

Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils
Neutrophils produce high levels of reactive oxygen species (ROS) by NADPH oxidase that are crucial for host defense but can lead to tissue injury when produced in excess. We previously described that proliferating cell nuclear antigen (PCNA), a nuclear scaffolding protein pivotal in DNA synthesis, controls neutrophil survival through its cytosolic association with procaspases. We herein showed that PCNA associated with p47phox, a key subunit of NADPH oxidase, and that this association regulated ROS production. Surface plasmon resonance and crystallography techniques demonstrated that the interdomain-connecting loop of PCNA...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Ohayon, D., De Chiara, A., Dang, P. M.-C., Thieblemont, N., Chatfield, S., Marzaioli, V., Burgener, S. S., Mocek, J., Candalh, C., Pintard, C., Tacnet-Delorme, P., Renault, G., Lagoutte, I., Favier, M., Walker, F., Hurtado-Nedelec, M., Desplancq, D., Weis Tags: Innate Immunity and Inflammation Articles Source Type: research

Yeats4 drives ILC lineage commitment via activation of Lmo4 transcription
Innate lymphoid cells (ILCs) play critical roles in defending infections and maintaining mucosal homeostasis. All ILCs arise from common lymphoid progenitors (CLPs) in bone marrow. However, how CLPs stratify and differentiate into ILC lineages remains elusive. Here, we showed that Yeats4 is highly expressed in ILCs and their progenitors. Yeats4 conditional KO in the hematopoietic system causes decreased numbers of ILCs and impairs their effector functions. Moreover, Yeats4 regulates α4β7+ CLP differentiation toward common helper ILC progenitors (CHILPs). Mechanistically, Yeats4 recruits the Dot1l–RNA Pol I...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Liu, B., Yang, L., Zhu, X., Li, H., Zhu, P., Wu, J., Lu, T., He, L., Liu, N., Meng, S., Zhou, L., Ye, B., Tian, Y., Fan, Z. Tags: Articles Source Type: research

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion
Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Zarei, M., Du, H., Nassar, A. H., Yan, R. E., Giannikou, K., Johnson, S. H., Lam, H. C., Henske, E. P., Wang, Y., Zhang, T., Asara, J., Kwiatkowski, D. J. Tags: Solid Tumors Articles Source Type: research

Host conditioning with IL-1{beta} improves the antitumor function of adoptively transferred T cells
Host conditioning has emerged as an important component of effective adoptive cell transfer–based immunotherapy for cancer. High levels of IL-1β are induced by host conditioning, but its impact on the antitumor function of T cells remains unclear. We found that the administration of IL-1β increased the population size and functionality of adoptively transferred T cells within the tumor. Most importantly, IL-1β enhanced the ability of tumor-specific T cells to trigger the regression of large, established B16 melanoma tumors in mice. Mechanistically, we showed that the increase in T cell numbers was asso...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Lee, P.-H., Yamamoto, T. N., Gurusamy, D., Sukumar, M., Yu, Z., Hu-Li, J., Kawabe, T., Gangaplara, A., Kishton, R. J., Henning, A. N., Vodnala, S. K., Germain, R. N., Paul, W. E., Restifo, N. P. Tags: Innate Immunity and Inflammation, Tumor Immunology Articles Source Type: research

The Nlrp6 inflammasome is not required for baseline colonic inner mucus layer formation or function
We report that isolated colonic goblet cells express components of several inflammasomes; however, analysis of IML properties in multiple inflammasome-deficient mice, including littermate-controlled Nlrp6–/–, detect a functional IML barrier in all strains. Analysis of mice lacking inflammasome substrate cytokines identifies a defective IML in Il18–/– mice, but this phenotype is ultimately traced to a microbiota-driven, Il18-independent effect. Analysis of phenotypic transfer between IML-deficient and IML-intact mice finds that the Bacteroidales family S24-7 (Muribaculaceae) and genus Adlercrutzia co...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Volk, J. K., Nyström, E. E. L., van der Post, S., Abad, B. M., Schroeder, B. O., Johansson, A., Svensson, F., Jäverfelt, S., Johansson, M. E. V., Hansson, G. C., Birchenough, G. M. H. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense, Mucosal Immunology Articles Source Type: research

Endothelial IQGAP1 regulates leukocyte transmigration by directing the LBRC to the site of diapedesis
Transendothelial migration (TEM) of leukocytes across the endothelium is critical for inflammation. In the endothelium, TEM requires the coordination of membrane movements and cytoskeletal interactions, including, prominently, recruitment of the lateral border recycling compartment (LBRC). The scaffold protein IQGAP1 was recently identified in a screen for LBRC-interacting proteins. Knockdown of endothelial IQGAP1 disrupted the directed movement of the LBRC and substantially reduced leukocyte TEM. Expression of truncated IQGAP1 constructs demonstrated that the calponin homology domain is required for IQGAP1 localization to...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Sullivan, D. P., Dalal, P. J., Jaulin, F., Sacks, D. B., Kreitzer, G., Muller, W. A. Tags: Cardiovascular Biology, Innate Immunity and Inflammation Articles Source Type: research

Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis
The NLRP3 inflammasome is critical for EAE pathogenesis; however, the role of gasdermin D (GSDMD), a newly identified pyroptosis executioner downstream of NLRP3 inflammasome, in EAE has not been well defined. Here, we observed that the levels of GSDMD protein were greatly enhanced in the CNS of EAE mice, especially near the areas surrounding blood vessels. GSDMD was required for the pathogenesis of EAE, and GSDMD deficiency in peripheral myeloid cells impaired the infiltration of immune cells into the CNS, leading to the suppression of neuroinflammation and demyelination. Furthermore, the loss of GSDMD reduced the activati...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Li, S., Wu, Y., Yang, D., Wu, C., Ma, C., Liu, X., Moynagh, P. N., Wang, B., Hu, G., Yang, S. Tags: Neuroinflammation, Innate Immunity and Inflammation Articles Source Type: research

Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model
Chronic activation of brain innate immunity is a prominent feature of Alzheimer’s disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, and the requirement of a particular glial cell type in neurodegeneration, are still unclear. Here we demonstrate that microglia-mediated damage, rather than pathological tau-induced direct neurotoxicity, is the leading force driving neurodegeneration in a tauopathy mouse model. Importantly, the progression of ptau pathology is also driven by microglia. In addition, we...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Shi, Y., Manis, M., Long, J., Wang, K., Sullivan, P. M., Remolina Serrano, J., Hoyle, R., Holtzman, D. M. Tags: Neuroinflammation, Innate Immunity and Inflammation, Neuroscience Articles Source Type: research

TGF{beta} signaling in germinal center B cells promotes the transition from light zone to dark zone
B cells in germinal centers (GCs) cycle between light zone (LZ) and dark zone (DZ). The cues in the GC microenvironment that regulate the transition from LZ to DZ have not been well characterized. In Peyer’s patches (PPs), transforming growth factor-β (TGFβ) promotes IgA induction in activated B cells that can then differentiate into GC B cells. We show here that TGFβ signaling occurs in B cells in GCs and is distinct from signaling that occurs in activated B cells in PPs. Whereas in activated B cells TGFβ signaling is required for IgA induction, in the GC it was instead required for the transitio...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Albright, A. R., Kabat, J., Li, M., Raso, F., Reboldi, A., Muppidi, J. R. Tags: Mucosal Immunology Articles Source Type: research

Corticospinal circuit remodeling after central nervous system injury is dependent on neuronal activity
The remodeling of supraspinal axonal circuits mediates functional recovery after spinal cord injury. This process critically depends on the selection of appropriate synaptic connections between cortical projection and spinal relay neurons. To unravel the principles that guide this target selection, we used genetic and chemogenetic tools to modulate NMDA receptor (NMDAR) integrity and function, CREB-mediated transcription, and neuronal firing of relay neurons during injury-induced corticospinal remodeling. We show that NMDAR signaling and CREB-mediated transcription maintain nascent corticospinal tract (CST)–relay neu...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Bradley, P. M., Denecke, C. K., Aljovic, A., Schmalz, A., Kerschensteiner, M., Bareyre, F. M. Tags: Neuroscience Brief Definitive Reports Source Type: research

Clearance of cerebrospinal fluid from the sacral spine through lymphatic vessels
The pathways of circulation and clearance of cerebrospinal fluid (CSF) in the spine have yet to be elucidated. We have recently shown with dynamic in vivo imaging that routes of outflow of CSF in mice occur along cranial nerves to extracranial lymphatic vessels. Here, we use near-infrared and magnetic resonance imaging to demonstrate the flow of CSF tracers within the spinal column and reveal the major spinal pathways for outflow to lymphatic vessels in mice. We found that after intraventricular injection, a spread of CSF tracers occurs within both the central canal and the spinal subarachnoid space toward the caudal end o...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Ma, Q., Decker, Y., Müller, A., Ineichen, B. V., Proulx, S. T. Tags: Cardiovascular Biology, Neuroscience Brief Definitive Reports Source Type: research

An anti-CRF antibody suppresses the HPA axis and reverses stress-induced phenotypes
Hypothalamic–pituitary–adrenal (HPA) axis dysfunction contributes to numerous human diseases and disorders. We developed a high-affinity monoclonal antibody, CTRND05, targeting corticotropin-releasing factor (CRF). In mice, CTRND05 blocks stress-induced corticosterone increases, counteracts effects of chronic variable stress, and induces other phenotypes consistent with suppression of the HPA axis. CTRND05 induces skeletal muscle hypertrophy and increases lean body mass, effects not previously reported with small-molecule HPA-targeting pharmacologic agents. Multiorgan transcriptomics demonstrates broad HPA axis...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Futch, H. S., McFarland, K. N., Moore, B. D., Kuhn, M. Z., Giasson, B. I., Ladd, T. B., Scott, K. A., Shapiro, M. R., Nosacka, R. L., Goodwin, M. S., Ran, Y., Cruz, P. E., Ryu, D. H., Croft, C. L., Levites, Y., Janus, C., Chakrabarty, P., Judge, A. R., Br Tags: Neuroscience, Metabolism Brief Definitive Reports Source Type: research

IL-2 production by self-reactive CD4 thymocytes scales regulatory T cell generation in the thymus
Regulatory T (T reg) cells, a specialized subset of CD4+ T cells, are essential to prevent fatal autoimmunity. Expression of the T reg lineage-defining transcription factor Foxp3, and therefore their differentiation in the thymus, is dependent upon T cell receptor (TCR) and interleukin-2 (IL-2) signaling. Here, we report that the majority of IL-2–producing cells in the thymus are mature CD4 single-positive (CD4SP) thymocytes and that continuous IL-2 production sustained thymic T reg cell generation and control of systemic immune activation. Furthermore, single-cell RNA sequencing analysis of CD4 thymocyte subsets rev...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Hemmers, S., Schizas, M., Azizi, E., Dikiy, S., Zhong, Y., Feng, Y., Altan-Bonnet, G., Rudensky, A. Y. Tags: Autoimmunity, Tolerance Brief Definitive Reports Source Type: research

Gasdermins and their role in immunity and inflammation
The gasdermins are a family of pore-forming proteins recently implicated in the immune response. One of these proteins, gasdermin D (GSDMD), has been identified as the executioner of pyroptosis, an inflammatory form of lytic cell death that is induced upon formation of caspase-1–activating inflammasomes. The related proteins GSDME and GSDMA have also been implicated in autoimmune diseases and certain cancers. Most gasdermin proteins are believed to have pore-forming capabilities. The best-studied member, GSDMD, controls the release of the proinflammatory cytokines IL-1ß and IL-18 and pyroptotic cell death. Beca...
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Orning, P., Lien, E., Fitzgerald, K. A. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Review Source Type: research

Arkaitz Carracedo: If the scientific question is good, the result will be interesting
Arkaitz Carracedo is a principal investigator at the Association for Cooperative Research in Biosciences (CIC bioGUNE) in Spain; his laboratory focuses on signaling and metabolic alterations in cancer. Arkaitz has investigated the regulation of fatty acid oxidation in cancer cells and how these changes could be manipulated therapeutically. We chatted with Arkaitz to find out about his career in science so far. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - November 3, 2019 Category: Internal Medicine Authors: Houston, S. Tags: People & amp; Ideas Source Type: research