Zhu and Lobato et al. uncovered the pathology of hereditary neuropathy caused by sorbitol dehydrogenase deficiency and provided a potential treatment strategy by using an aldose reductase inhibitor, AT-007 (govorestat). The cover image depicts the Drosophila flight muscle neuromuscular junctions immunolabeled with a synaptic active zone marker (Bruchpilot) and a neuronal membrane marker (horseradish peroxidase). Image credit: Tijana Canic, Yi Zhu, and Amanda Lobato.
Fatty acid binding protein 4 (FABP4) is a lipid chaperone secreted from adipocytes upon stimulation of lipolysis. Circulating FABP4 levels strongly correlate with obesity and metabolic pathologies in experimental models and humans. While adipocytes have been presumed to be the major source of hormonal FABP4, this question has not been addressed definitively in vivo. We generated mice with Fabp4 deletion in cells known to express the gene; adipocytes (Adipo-KO), endothelial cells (Endo-KO), myeloid cells (Myeloid-KO), and the whole body (Total-KO) to examine the contribution of these cell types to basal and stimulated plasma FABP4 levels. Unexpectedly, baseline plasma FABP4 was not significantly reduced in Adipo-KO mice, whereas Endo-KO mice showed ~87% reduction versus wildtype controls. In contrast, Adipo-KO mice exhibited ~62% decreased induction of FABP4 responses to lipolysis, while Endo-KO mice showed only mildly decreased induction, indicating that adipocytes are the main source of increases in FABP4 during lipolysis. We did not detect any myeloid contribution to circulating FABP4. Surprisingly, despite the nearly intact induction of FABP4, Endo-KO mice showed blunted lipolysis-induced insulin secretion, identical to Total-KO mice. We conclude that the endothelium is the major source of baseline hormonal FABP4 and is required for the insulin response to lipolysis.
Karen E. Inouye, Kacey J. Prentice, Alexandra Lee, Zeqiu B. Wang, Carla Dominguez-Gonzalez, Mu Xian Chen, Jillian K. Riveros, M. Furkan Burak, Grace Y. Lee, Gokhan S. Hotamisligil
During alveolar repair, alveolar type 2 (AT2) epithelial cell progenitors rapidly proliferate and differentiate into flat type 1 alveolar epithelial cells. Failure of normal alveolar repair mechanisms can lead to loss of alveolar structure (emphysema) or development of fibrosis, depending on the type and severity of injury. To test if β1-containing integrins are required during repair following acute injury, we administered E. coli lipopolysaccharide (LPS) by intratracheal injection to mice with a post-developmental deletion of β1 integrin in AT2 cells. While control mice recovered from LPS injury without structural abnormalities, β1-deficient mice had more severe inflammation and developed emphysema. In addition, recovering alveoli were repopulated with an abundance of rounded epithelial cells co-expressing type 2, type 1, and mixed intermediate cell state markers, with few mature type 1 cells. β1-deficient AT2 cells showed persistently increased proliferation after injury, which was blocked by inhibiting NF-kB activation in these cells. Lineage tracing experiments revealed that β1-deficient AT2 cells failed to differentiate into mature type 1 alveolar epithelial cells. Together, these findings demonstrate that functional alveolar repair after injury with terminal alveolar epithelial differentiation requires β1-containing integrins.
Jennifer M.S. Sucre, Fabian Bock, Nicholas M. Negretti, John T. Benjamin, Peter M. Gulleman, Xinyu Dong, Kimberly T. Ferguson, Christopher S. Jetter, Wei Han, Yang Liu, Seunghyi Kook, Jason J. Gokey, Susan H. Guttentag, Jonathan A. Kropski, Timothy S. Blackwell, Roy Zent, Erin J. Plosa
Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Increased platelet counts and activation are observed during the course of KD, and elevated platelet counts are associated with higher risks of developing intravenous immunoglobulin (IVIG) resistance and coronary artery (CA) aneurysms. However, the role of platelets in KD pathogenesis remains unclear. Here, we analyzed transcriptomics data generated from the whole blood of KD patients and discovered changes in the expression of platelet-related genes during acute KD. In the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis, LCWE injection increased platelet counts and the formation of monocyte-platelet aggregates (MPAs), upregulated the concentration of soluble P-selectin, and increased circulating thrombopoietin (TPO) and interleukin (IL)-6. Furthermore, platelet counts correlated with the severity of cardiovascular inflammation. Genetic depletion of platelets (mpl–/– mice) or treatment with anti-CD42b antibody led to a significant reduction of LCWE-induced cardiovascular lesions. Furthermore, in the mouse model, platelets promoted vascular inflammation via the formation of MPAs, which amplify IL-1β production. Altogether, our results indicate that platelet activation exacerbates the development of cardiovascular lesions in a murine model of KD vasculitis. These findings enhance our understanding of KD vasculitis pathogenesis and highlight MPAs, which are known to enhance IL-1β production, as a potential therapeutic target for this disorder.
Begüm Kocatürk, Youngho Lee, Nobuyuki Nosaka, Masanori Abe, Daisy Martinon, Malcolm E. Lane, Debbie Moreira, Shuang Chen, Michael C. Fishbein, Rebecca A. Porritt, Bernardo S. Franklin, Magali Noval Rivas, Moshe Arditi
Stimulating the Gq-coupled P2Y2 receptor (P2ry2) lowers blood pressure. Global knockout of P2ry2 increases blood pressure. Vascular and renal mechanisms are believed to participate in P2ry2 effects on blood pressure. To isolate the role of the kidneys in P2ry2 effects on blood pressure and to reveal the molecular and cellular mechanisms of this action, we test here the necessity of the P2ry2 and the sufficiency of Gq-dependent signaling in renal principal cells to the regulation of the epithelial Na+ channel (ENaC), sodium excretion and blood pressure. Activating P2ry2 in littermate controls but not principal cell specific P2ry2 knockout mice decreases the activity of ENaC in renal tubules. Moreover, deletion of P2ry2 in principal cells abolishes increases in sodium excretion in response to stimulation of P2ry2 and compromises the normal ability to excrete a sodium load. Consequently, principal cell specific knockout of P2ry2 prevents decreases in blood pressure in response to P2ry2 stimulation in the DOCA-salt model of hypertension. In wild-type littermate controls, such stimulation decreases blood pressure in this model of hypertension by promoting a natriuresis. Pharmacogenetic activation of Gq exclusively in principal cells using targeted expression of Gq-DREADD (Designer Receptors Exclusively Activated by Designer Drugs; GqD) and clozapine N-oxide (CNO) decreases the activity of ENaC in renal tubules promoting a natriuresis that lowers elevated blood pressure in the DOCA-salt model of hypertension. These findings demonstrate that the kidneys play a major role in decreasing blood pressure in response to P2ry2 activation, and that inhibition of ENaC activity in response to P2ry2 mediated Gq signaling lowers blood pressure by increasing renal sodium excretion.
Antonio G. Soares, Jorge Contreras, Elena Mironova, Crystal R. Archer, James D. Stockand, Tarek M. Abd El-Aziz
Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20-30% of OS carry amplification of chromosome 8q24, which harbors the oncogene c-Myc and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of Myc to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox;(LSL)-c-MycT58A;p53fl/+ knock-in genetically engineered mouse model (GEMM). Phenotypically, the Myc knockin-GEMM had rapid tumor development with a high incidence of metastasis. Myc-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated Myc OS. We established that hyperactivation of Myc leads to an immune-depleted TME in OS demonstrated by the reduced number of leukocytes, particularly macrophages. Myc-hyperactivation leads to the downregulation of macrophage-colony-stimulating factor (CSF-1), through increased miR-17/20a expression, causing a reduction of macrophage population in the TME of OS. Furthermore, we developed cell lines from the GEMM tumors, including a dTAG-Myc model system, which validated our Myc-dependent findings both in vitro and in vivo. Our studies utilized innovative, and clinically relevant models to identify a novel molecular mechanism through which Myc regulates the profile and function of the osteosarcoma immune landscape.
Bikesh K. Nirala, Tajhal D. Patel, Lyazat Kurenbekova, Ryan Shuck, Atreyi Dasgupta, Nino Rainusso, Cristian Coarfa, Jason T. Yustein