Abstract
Though recent reports suggest that neutrophil extracellular traps (NETs) are a source of antigenic nucleic acids in systemic lupus erythematosus (SLE), we recently showed that inhibition of NETs by targeting the NADPH oxidase complex via cytochrome b-245, β polypeptide (
Authors
Rachael A. Gordon, Jan M. Herter, Florencia Rosetti, Allison M. Campbell, Hiroshi Nishi, Michael Kashgarian, Sheldon I. Bastacky, Anthony Marinov, Kevin M. Nickerson, Tanya N. Mayadas, Mark J. Shlomchik
Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression
Abstract
Advanced cancer induces fundamental changes in metabolism and promotes cardiac atrophy and heart failure. We discovered systemic insulin deficiency in cachectic cancer patients. Similarly, mice with advanced B16F10 melanoma (B16F10-TM) or colon 26 carcinoma (C26-TM) displayed decreased systemic insulin associated with marked cardiac atrophy, metabolic impairment, and function. B16F10 and C26 tumors decrease systemic insulin via high glucose consumption, lowering pancreatic insulin production and producing insulin-degrading enzyme. As tumor cells consume glucose in an insulin-independent manner, they shift glucose away from cardiomyocytes. Since cardiomyocytes in both tumor models remained insulin responsive, low-dose insulin supplementation by subcutaneous implantation of insulin-releasing pellets improved cardiac glucose uptake, atrophy, and function, with no adverse side effects. In addition, by redirecting glucose to the heart in addition to other organs, the systemic insulin treatment lowered glucose usage by the tumor and thereby decreased tumor growth and volume. Insulin corrected the cancer-induced reduction in cardiac Akt activation and the subsequent overactivation of the proteasome and autophagy. Thus, cancer-induced systemic insulin depletion contributes to cardiac wasting and failure and may promote tumor growth. Low-dose insulin supplementation attenuates these processes and may be supportive in cardio-oncologic treatment concepts.
Authors
James T. Thackeray, Stefan Pietzsch, Britta Stapel, Melanie Ricke-Hoch, Chun-Wei Lee, Jens P. Bankstahl, Michaela Scherr, Jörg Heineke, Gesine Scharf, Arash Haghikia, Frank M. Bengel, Denise Hilfiker-Kleiner
Abstract
DCs are necessary and sufficient for induction of allergic airway inflammation. CD11b+ DCs direct the underlying Th2 immunity, but debate surrounds the function of CD103+ DCs in lung immunity and asthma after an allergic challenge. We challenged
Authors
Laura Conejero, Sofía C. Khouili, Sarai Martínez-Cano, Helena M. Izquierdo, Paola Brandi, David Sancho
Abstract
Metabolic dysregulation promotes cancer growth through not only energy production, but also epigenetic reprogramming. Here, we report that a critical node in methyl donor metabolism, nicotinamide N-methyltransferase (NNMT), ranked among the most consistently overexpressed metabolism genes in glioblastoma relative to normal brain. NNMT was preferentially expressed by mesenchymal glioblastoma stem cells (GSCs). NNMT depletes S-adenosyl methionine (SAM), a methyl donor generated from methionine. GSCs contained lower levels of methionine, SAM, and nicotinamide, but they contained higher levels of oxidized nicotinamide adenine dinucleotide (NAD+) than differentiated tumor cells. In concordance with the poor prognosis associated with DNA hypomethylation in glioblastoma, depletion of methionine, a key upstream methyl group donor, shifted tumors toward a mesenchymal phenotype and accelerated tumor growth. Targeting NNMT expression reduced cellular proliferation, self-renewal, and in vivo tumor growth of mesenchymal GSCs. Supporting a mechanistic link between NNMT and DNA methylation, targeting NNMT reduced methyl donor availability, methionine levels, and unmethylated cytosine, with increased levels of DNA methyltransferases, DNMT1 and DNMT3A. Supporting the clinical significance of these findings, NNMT portended poor prognosis for glioblastoma patients. Collectively, our findings support NNMT as a GSC-specific therapeutic target in glioblastoma by disrupting oncogenic DNA hypomethylation.
Authors
Jinkyu Jung, Leo J.Y. Kim, Xiuxing Wang, Qiulian Wu, Tanwarat Sanvoranart, Christopher G. Hubert, Briana C. Prager, Lisa C. Wallace, Xun Jin, Stephen C. Mack, Jeremy N. Rich
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for a variety of hematologic malignances, yet its efficacy is impeded by the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production, and migration of alloreactive donor T cells. Hence, strategies to limit GVHD are highly desirable. Ceramides are known to contribute to inflammation and autoimmunity. However, their involvement in T-cell responses to alloantigens is undefined. In the current study, we specifically characterized the role of ceramide synthase 6 (CerS6) after allo-HCT using genetic and pharmacologic approaches. We found that CerS6 was required for optimal T cell activation, proliferation, and cytokine production in response to alloantigen and for subsequent induction of GVHD. However, CerS6 was partially dispensable for the T cell–mediated antileukemia effect. At the molecular level, CerS6 was required for efficient TCR signal transduction, including tyrosine phosphorylation, ZAP-70 activation, and PKCθ/TCR colocalization. Impaired generation of C16-ceramide was responsible for diminished allogeneic T cell responses. Furthermore, targeting CerS6 using a specific inhibitor significantly reduced T cell activation in mouse and human T cells in vitro. Our study provides a rationale for targeting CerS6 to control GVHD, which would enhance the efficacy of allo-HCT as an immunotherapy for hematologic malignancies in the clinic.
Authors
M. Hanief Sofi, Jessica Heinrichs, Mohammed Dany, Hung Nguyen, Min Dai, David Bastian, Steven Schutt, Yongxia Wu, Anusara Daenthanasanmak, Salih Gencer, Aleksandra Zivkovic, Zdzislaw Szulc, Holger Stark, Chen Liu, Ying-Jun Chang, Besim Ogretmen, Xue-Zhong Yu
Abstract
Many effector mechanisms of neutrophils have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) have been assigned a particularly detrimental role. Here we investigated the functional impact of neutrophils and NETs on a mouse model of lupus triggered by intraperitoneal injection of the cell death–inducing alkane pristane. Pristane-induced lupus (PIL) was aggravated in 2 mouse strains with impaired induction of NET formation, i.e., NOX2-deficient (
Authors
Deborah Kienhöfer, Jonas Hahn, Julia Stoof, Janka Zsófia Csepregi, Christiane Reinwald, Vilma Urbonaviciute, Caroline Johnsson, Christian Maueröder, Malgorzata J. Podolska, Mona H. Biermann, Moritz Leppkes, Thomas Harrer, Malin Hultqvist, Peter Olofsson, Luis E. Munoz, Attila Mocsai, Martin Herrmann, Georg Schett, Rikard Holmdahl, Markus H. Hoffmann
Abstract
Many extremely preterm infants (born before 28 gestational weeks [GWs]) develop cognitive impairment in later life, although the underlying pathogenesis is not yet completely understood. Our examinations of the developing human neocortex confirmed that neuronal migration continues beyond 23 GWs, the gestational week at which extremely preterm infants have live births. We observed larger numbers of ectopic neurons in the white matter of the neocortex in human extremely preterm infants with brain injury and hypothesized that altered neuronal migration may be associated with cognitive impairment in later life. To confirm whether preterm brain injury affects neuronal migration, we produced brain damage in mouse embryos by occluding the maternal uterine arteries. The mice showed delayed neuronal migration, ectopic neurons in the white matter, altered neuronal alignment, and abnormal corticocortical axonal wiring. Similar to human extremely preterm infants with brain injury, the surviving mice exhibited cognitive deficits. Activation of the affected medial prefrontal cortices of the surviving mice improved working memory deficits, indicating that decreased neuronal activity caused the cognitive deficits. These findings suggest that altered neuronal migration altered by brain injury might contribute to the subsequent development of cognitive impairment in extremely preterm infants.
Authors
Ken-ichiro Kubo, Kimiko Deguchi, Taku Nagai, Yukiko Ito, Keitaro Yoshida, Toshihiro Endo, Seico Benner, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Minkyung Shin, Yuki Matsunaga, Kanehiro Hayashi, Masaki Kakeyama, Chiharu Tohyama, Kenji F. Tanaka, Kohichi Tanaka, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Yukio Hirata, Barbara Antalffy, Dawna D. Armstrong, Kiyofumi Yamada, Ken Inoue, Kazunori Nakajima
Abstract
Brown adipose tissue (BAT) is a central organ that acts to increase energy expenditure; its regulatory factors could be clinically useful in the treatment of obesity. Tetrahydrobiopterin (BH4) is an essential cofactor of tyrosine hydroxylase and nitric oxide synthase (NOS). Although BH4 regulates the known regulatory factors of BAT, such as noradrenaline (NA) and NO, participation of BH4 in BAT function remains unclear. In the present study, we investigate the role of BH4 in the regulation of BAT. Hph-1 mice, a mouse model of BH4 deficiency, exhibit obesity, adiposity, glucose intolerance, insulin resistance, and impaired BAT function. Impaired BAT function was ameliorated together with systemic metabolic disturbances by BAT transplantation from BH4-sufficient mice (control mice) into BH4-deficient mice, strongly suggesting that BH4-induced BAT has a critical role in the regulation of systemic energy metabolism. Both NA derived from the sympathetic nerve and NO derived from endothelial NOS in the blood vessels participate in the regulation of BH4. In addition, a direct effect of BH4 in the stimulation of brown adipocytes via NO is implicated. Taken together, BH4 activates BAT and regulates systemic energy metabolism; this suggests an approach for metabolic disorders, such as obesity and diabetes.
Authors
Yasuo Oguri, Yoshihito Fujita, Abulizi Abudukadier, Akiko Ohashi, Tsuyoshi Goto, Futoshi Furuya, Akio Obara, Toru Fukushima, Naomi Matsuo, Minji Kim, Masaya Hosokawa, Teruo Kawada, Hiroyuki Hasegawa, Nobuya Inagaki
Abstract
Fibrotic lung disease, most notably idiopathic pulmonary fibrosis (IPF), is thought to result from aberrant wound-healing responses to repetitive lung injury. Increased vascular permeability is a cardinal response to tissue injury, but whether it is mechanistically linked to lung fibrosis is unknown. We previously described a model in which exaggeration of vascular leak after lung injury shifts the outcome of wound-healing responses from normal repair to pathological fibrosis. Here we report that the fibrosis produced in this model is highly dependent on thrombin activity and its downstream signaling pathways. Direct thrombin inhibition with dabigatran significantly inhibited protease-activated receptor-1 (PAR1) activation, integrin αvβ6 induction, TGF-β activation, and the development of pulmonary fibrosis in this vascular leak–dependent model. We used a potentially novel imaging method — ultashort echo time (UTE) lung magnetic resonance imaging (MRI) with the gadolinium-based, fibrin-specific probe EP-2104R — to directly visualize fibrin accumulation in injured mouse lungs, and to correlate the antifibrotic effects of dabigatran with attenuation of fibrin deposition. We found that inhibition of the profibrotic effects of thrombin can be uncoupled from inhibition of hemostasis, as therapeutic anticoagulation with warfarin failed to downregulate the PAR1/αvβ6/TGF-β axis or significantly protect against fibrosis. These findings have direct and important clinical implications, given recent findings that warfarin treatment is not beneficial in IPF, and the clinical availability of direct thrombin inhibitors that our data suggest could benefit these patients.
Authors
Barry S. Shea, Clemens K. Probst, Patricia L. Brazee, Nicholas J. Rotile, Francesco Blasi, Paul H. Weinreb, Katharine E. Black, David E. Sosnovik, Elizabeth M. Van Cott, Shelia M. Violette, Peter Caravan, Andrew M. Tager
Abstract
Mechanisms of atherogenesis have been studied extensively in genetically engineered mice with disturbed cholesterol metabolism such as those lacking either the LDL receptor (
Authors
Srinivas D. Sithu, Marina V. Malovichko, Krista A. Riggs, Nalinie S. Wickramasinghe, Millicent G. Winner, Abhinav Agarwal, Rihab E. Hamed-Berair, Anuradha Kalani, Daniel W. Riggs, Aruni Bhatnagar, Sanjay Srivastava
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