1. [Science] 1 November 2013 vol 342, issue 6158, pages 521-660

9. [Science Signaling] 29 October 2013 Vol 6, Issue 299

10. The use of induced pluripotent stem cells (iPSCs) has been postulated to be the most effective strategy for developing pati ent-specific respiratory epithelial cells, which may be valuable for lung-related cell therapy and lung tissue engineering. W e generated a relatively homogeneous population of alveolar epithelial type II (AETII) and type I (AETI) cells from human i PSCs that had phenotypic properties similar to those of mature human AETII and AETI cells. We used these cells to explor e whether lung tissue can be regenerated in vitro. Consistent with an AETII phenotype, we found that up to 97% of cells w ere positive for surfactant protein C, 95% for mucin-1, 93% for surfactant protein B, and 89% for the epithelial marker CD5 4. Additionally, exposing induced AETII to a Wnt/β-catenin inhibitor (IWR-1) changed the iPSC-AETII–like phenotype to a p redominantly AETI-like phenotype. We found that of induced AET1 cells, more than 90% were positive for type I markers, T1α, and caveolin-1. Acellular lung matrices were prepared from whole rat or human adult lungs treated with decellularizati on reagents, followed by seeding these matrices with alveolar cells derived from human iPSCs. Under appropriate culture conditions, these progenitor cells adhered to and proliferated within the 3D lung tissue scaffold and displayed markers of d ifferentiated pulmonary epithelium.

11. Regulatory T (Treg) cells maintain immune homeostasis by limiting autoimmune and inflammatory responses. Treg differe ntiation, maintenance, and function are controlled by the transcription factor Foxp3. However, the exact molecular mechan isms underlying Treg cell regulation remain elusive. Here, we show that Treg cell–specific ablation of the E3 ubiquitin ligas e Itch in mice caused massive multiorgan lymphocyte infiltration and skin lesions, chronic T cell activation, and the develo pment of severe antigen-induced airway inflammation. Surprisingly, Foxp3 expression, homeostasis, and the in vitro and in vivo suppressive capability of Treg cells were not affected by Itch deficiency. We found that the expression of Th2 cytokine s by Treg cells was increased in the absence of Itch. Fate mapping revealed that a fraction of Treg cells lost Foxp3 expres sion independently of Itch. However, Th2 cytokines were excessively augmented in Itch –/– Foxp3-negative “ex-Treg” cells without altering the percentage of conversion. Targeted knockdown of Th2 transcriptional regulators in Itch –/– Treg cells pre vented Th2 cytokine production. The present study unveils a mechanism of Treg cell acquisition of Th2-like properties that is independent of Foxp3 function and Treg cell stability.

12. Diabetic microvascular complications have been considered to be mediated by a glucose-driven increase in mitochondrial superoxide anion production. Here, we report that superoxide production was reduced in the kidneys of a steptozotocin-in duced mouse model of type 1 diabetes, as assessed by in vivo real-time transcutaneous fluorescence, confocal microscop y, and electron paramagnetic resonance analysis. Reduction of mitochondrial biogenesis and phosphorylation of pyruvate dehydrogenase (PDH) were observed in kidneys from diabetic mice. These observations were consistent with an overall r eduction of mitochondrial glucose oxidation. Activity of AMPK, the major energy-sensing enzyme, was reduced in kidneys f rom both diabetic mice and humans. Mitochondrial biogenesis, PDH activity, and mitochondrial complex activity were resc ued by treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). AICAR treatm ent induced superoxide production and was linked with glomerular matrix and albuminuria reduction in the diabetic kidney. Furthermore, diabetic heterozygous superoxide dismutase 2 (Sod2 +/– ) mice had no evidence of increased renal disease, a nd Ampka2 –/– mice had increased albuminuria that was not reduced with AICAR treatment. Reduction of mitochondrial sup eroxide production with rotenone was sufficient to reduce AMPK phosphorylation in mouse kidneys. Taken together, these results demonstrate that diabetic kidneys have reduced superoxide and mitochondrial biogenesis and activation of AMPK enhances superoxide production and mitochondrial function while reducing disease activity.

19. KJKJ Modulation of NMDAR Subunit Expression by TRPM2 Channels Regulates Neuronal Vulnerability to Ischemic Cell Death Ishraq Alim1,2, Lucy Teves1, Rongwen Li1, Yasuo Mori4, and Michael Tymianski1,2,3 Abstract Neuronal vulnerability to ischemia is dependent on the balance between prosurvival and prodeath cellular signaling. In the latter, it is increasingly appreciated that toxic Ca2+ influx can occur not only via postsynaptic glutamate receptors, but also through other cation conductances. One such conductance, the Transient receptor potential melastatin type-2 (TRPM2) channel, is a nonspecific cation channel having homology to TRPM7, a conductance reported to play a key role in anoxic neuronal death. The role of TRPM2 conductances in ischemic Ca2+ influx has been difficult to study because of the lack of specific modulators. Here we used TRPM2-null mice (TRPM2−/−) to study how TRPM2 may modulate neuronal vulnerability to ischemia. TRPM2−/− mice subjected to transient middle cerebral artery occlusion exhibited smaller infarcts when compared with wild-type animals, suggesting that the absence of TRPM2 is neuroprotective. Surprisingly, field potentials (fEPSPs) recorded during redox modulation in brain slices taken from TRPM2−/− mice revealed increased excitability, a phenomenon normally associated with ischemic vulnerability, whereas wild-type fEPSPs were unaffected. The upregulation in fEPSP in TRPM2−/− neurons was blocked selectively by a GluN2A antagonist. This increase in excitability of TRPM2−/− fEPSPs during redox modulation depended on the upregulation and downregulation of GluN2A- and GluN2B-containing NMDARs, respectively, and on augmented prosurvival signaling via Akt and ERK pathways culminating in the inhibition of the proapoptotic factor GSK3β. Our results suggest that TRPM2 plays a role in downregulating prosurvival signals in central neurons and that TRPM2 channels may comprise a therapeutic target for preventing ischemic damage.

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23. BRIEF REVIEWS Little Peptide, Big Effects: The Role of LL-37 in Inflammation and Autoimmune Disease J. Michelle Kahlenberg and Mariana J. Kaplan J Immunol 2013 191:4895-4901; doi:10.4049/jimmunol.1302005 CUTTING EDGE Cutting Edge: Identification of the Thymic Stromal Lymphopoietin–Responsive Dendritic Cell Subset Critical for Initiation of Type 2 Contact Hypersensitivity Masayuki Kitajima and Steven F. Ziegler J Immunol 2013 191:4903-4907; published ahead of print October 11, 2013,doi:10.4049/jimmunol.1302175 Cutting Edge: Smad2 and Smad4 Regulate TGF-β– Mediated Il9 Gene Expression via EZH2 Displacement Aibo Wang, Deng Pan, Young-Hee Lee, Gustavo J. Martinez, Xin- hua Feng, and Chen Dong J Immunol 2013 191:4908-4912; published ahead of print October 9, 2013,doi:10.4049/jimmunol.1300433 Cutting Edge: Type 1 Diabetes Occurs despite Robust Anergy among Endogenous Insulin-Specific CD4 T Cells in NOD Mice Kristen E. Pauken, Jonathan L. Linehan, Justin A. Spanier, Nathanael L. Sahli,Lokesh A. Kalekar, Bryce A. Binstadt, James J. Moon, Daniel L. Mueller,Marc K. Jenkins, and Brian T. Fife J Immunol 2013 191:4913-4917; published ahead of print October 11, 2013,doi:10.4049/jimmunol.1301927 AUTOIMMUNITY Molecular Basis of 9G4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus Christopher Richardson, Asiya Seema Chida, Diana Adlowitz, Lin Silver, Erin Fox,Scott A. Jenks, Elise Palmer, Youliang Wang, Jamie Heimburg-Molinaro,Quan-Zhen Li, Chandra Mohan, Richard Cummings, Christopher Tipton,and Ignacio Sanz J Immunol 2013 191:4926-4939; published ahead of print October 9, 2013,doi:10.4049/jimmunol.1202263 Reduced Effectiveness of CD4 + Foxp3 + Regulatory T Cells in CD28-Deficient NOD.H-2h4 Mice Leads to Increased Severity of Spontaneous Autoimmune Thyroiditis Jason S. Ellis, So-Hee Hong, Habib Zaghouani, and Helen Braley-Mullen J Immunol 2013 191:4940-4949; published ahead of print October 4, 2013,doi:10.4049/jimmunol.1301253 T Cell–Independent Modulation of Experimental Autoimmune Encephalomyelitis in ADAP-Deficient Mice Swen Engelmann, Mauro Togni, Anja Thielitz, Peter Reichardt, Stefanie Kliche,Dirk Reinhold, Burkhart Schraven, and Annegret Reinhold J Immunol 2013 191:4950-4959; published ahead of print October 7, 2013,doi:10.4049/jimmunol.1203340 The Role of CD8 + T Cells and Their Local Interaction with CD4 + T Cells in Myelin Oligodendrocyte Glycoprotein 35–55 – Induced Experimental Autoimmune Encephalomyelitis Tina Leuenberger, Magdalena Paterka, Eva Reuter, Josephine Herz,Raluca A. Niesner, Helena Radbruch, Tobias Bopp, Frauke Zipp, and Volker Siffrin J Immunol 2013 191:4960-4968; published ahead of print October 11, 2013,doi:10.4049/jimmunol.1300822 Journal of Immunology

24. A Novel Disease-Modifying Antirheumatic Drug, Iguratimod, Ameliorates Murine Arthritis by Blocking IL-17 Signaling, Distinct from Methotrexate and Leflunomide Qiong Luo, Yang Sun, Wen Liu, Cheng Qian, Biao Jin, Feifei Tao, Yanhong Gu,Xingxin Wu, Yan Shen, and Qiang Xu J Immunol 2013 191:4969-4978; published ahead of print October 11, 2013,doi:10.4049/jimmunol.1300832 Reduced T Cell–Dependent Humoral Immune Response in Microsomal Prostaglandin E Synthase-1 Null Mice Is Mediated by Nonhematopoietic Cells Fumiaki Kojima, Andrey Frolov, Rahul Matnani, Jerold G. Woodward,and Leslie J. Crofford J Immunol 2013 191:4979-4988; published ahead of print October 14, 2013,doi:10.4049/jimmunol.1301942 INNATE IMMUNITY AND INFLAMMATION Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways Seong-Hwan Park, Kee Hun Do, Hye Jin Choi, Juil Kim, Ki-Hyung Kim, Jiyeon Park,Chang Gyu Oh, and Yuseok Moon J Immunol 2013 191:5170-5181; published ahead of print October 4, 2013,doi:10.4049/jimmunol.1301145 Wnt6 Is Expressed in Granulomatous Lesions of Mycobacterium tuberculosis–Infected Mice and Is Involved in Macrophage Differentiation and Proliferation Kolja Schaale, Julius Brandenburg, Andreas Kispert, Michael Leitges,Stefan Ehlers, and Norbert Reiling J Immunol 2013 191:5182-5195; published ahead of print October 11, 2013,doi:10.4049/jimmunol.1201819 Lipopolysaccharide Stimulates Platelets through an IL-1β Autocrine Loop G. Thomas Brown, Padmini Narayanan, Wei Li, Roy L. Silverstein, and Thomas M. McIntyre J Immunol 2013 191:5196-5203; published ahead of print September 30, 2013,doi:10.4049/jimmunol.1300354 Phenotypic Polarization of Activated Astrocytes: The Critical Role of Lipocalin-2 in the Classical Inflammatory Activation of Astrocytes Eunha Jang, Jong-Heon Kim, Shinrye Lee, Jae-Hong Kim, Jung- Wan Seo,Myungwon Jin, Maan-Gee Lee, Il-Sung Jang, Won-Ha Lee, and Kyoungho Suk J Immunol 2013 191:5204-5219; published ahead of print October 2, 2013,doi:10.4049/jimmunol.1301637 IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice Tatiana Paula T. Ferreira, Ana Carolina S. de Arantes,Caio Victor M. F. do Nascimento, Priscilla C. Olsen, Patrícia G. Trentin,Patricia R. M. Rocco, Cory M. Hogaboam, Raj K. Puri, Marco Aurélio Martins,and Patrícia Machado Rodrigues e Silva J Immunol 2013 191:5220-5229; published ahead of print October 16, 2013,doi:10.4049/jimmunol.1203551 Mitochondrial Reactive Oxygen Species Induces NLRP3- Dependent Lysosomal Damage and Inflammasome Activation Michelle E. Heid, Peter A. Keyel, Christelle Kamga, Sruti Shiva, Simon C. Watkins,and Russell D. Salter J Immunol 2013 191:5230-5238; published ahead of print October 2, 2013,doi:10.4049/jimmunol.1301490

25. Salmonella Infection Induces Recruitment of Caspase-8 to the Inflammasome To Modulate IL-1β Production Si Ming Man, Panagiotis Tourlomousis, Lee Hopkins, Tom P. Monie,Katherine A. Fitzgerald, and Clare E. Bryant J Immunol 2013 191:5239-5246; published ahead of print October 11, 2013,doi:10.4049/jimmunol.1301581 Targeting F Box Protein Fbxo3 To Control Cytokine-Driven Inflammation Rama K. Mallampalli, Tiffany A. Coon, Jennifer R. Glasser, Claire Wang,Sarah R. Dunn, Nathaniel M. Weathington, Jing Zhao, Chunbin Zou, Yutong Zhao,and Bill B. Chen J Immunol 2013 191:5247-5255; published ahead of print October 11, 2013,doi:10.4049/jimmunol.1300456 Genome-Wide siRNA Screen Reveals a New Cellular Partner of NK Cell Receptor KIR2DL4: Heparan Sulfate Directly Modulates KIR2DL4-Mediated Responses Michael Brusilovsky, Moti Cordoba, Benyamin Rosental, Oren Hershkovitz,Mark D. Andrake, Anna Pecherskaya, Margret B. Einarson, Yan Zhou,Alex Braiman, Kerry S. Campbell, and Angel Porgador J Immunol 2013 191:5256-5267; published ahead of print October 14, 2013,doi:10.4049/jimmunol.130207 MOLECULAR AND STRUCTURAL IMMUNOLOGY MAIT Recognition of a Stimulatory Bacterial Antigen Bound to MR1 Jacinto López-Sagaseta, Charles L. Dulberger, Amanda McFedries,Mark Cushman, Alan Saghatelian, and Erin J. Adams J Immunol 2013 191:5268-5277; published ahead of print October 9, 2013,doi:10.4049/jimmunol.1301958 TUMOR IMMUNOLOGY Cooperativity of CD44 and CD49d in Leukemia Cell Homing, Migration, and Survival Offers a Means for Therapeutic Attack Vibuthi Singh, Ulrike Erb, and Margot Zöller J Immunol 2013 191:5304-5316; published ahead of print October 14, 2013,doi:10.4049/jimmunol.1301543

26. Targeting F Box Protein Fbxo3 To Control Cytokine-Driven Inflammation Rama K. Mallampalli*Rama K. Mallampalli*,†‡§, Tiffany A. Coon*,†, Jennifer R. Glasser*,†,Claire Wang*,†, Sarah R. Dunn*,†, Nathaniel M. Weathington*,†, Jing Zhao*,†,Chunbin Zou*,†, Yutong Zhao*,† and Bill B. Chen*,††‡§Tiffany A. Coon*†Jennifer R. Glasser*†Claire Wang*†Sarah R. Dunn*†Nathaniel M. Weathington*†Jing Zhao*†Chunbin Zou*†Yutong Zhao*†Bill B. Chen*† * Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213; † Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213; ‡ Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15213; and § Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15213 Cytokine-driven inflammation underlies the pathobiology of a wide array of infectious and immune- related disorders. The TNFR-associated factor (TRAF) proteins have a vital role in innate immunity by conveying signals from cell surface receptors to elicit transcriptional activation of genes encoding proinflammatory cytokines. We discovered that a ubiquitin E3 ligase F box component, termed Fbxo3, potently stimulates cytokine secretion from human inflammatory cells by mediating the degradation of the TRAF inhibitory protein, Fbxl2. Analysis of the Fbxo3 C-terminal structure revealed that the bacterial-like ApaG molecular signature was indispensible for mediating Fbxl2 disposal and stimulating cytokine secretion. By targeting this ApaG motif, we developed a highly unique, selective genus of small-molecule Fbxo3 inhibitors that by reducing TRAF protein levels, potently inhibited cytokine release from human blood mononuclear cells. The Fbxo3 inhibitors effectively lessened the severity of viral pneumonia, septic shock, colitis, and cytokine-driven inflammation systemically in murine models. Thus, pharmacological targeting of Fbxo3 might be a promising strategy for immune-related disorders characterized by a heightened host inflammatory response.