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Kanti et al. report that adipose triglyceride lipase, the rate-limiting enzyme for intracellular lipolysis, is critical for club cell–driven regeneration of bronchiolar epithelia in mice. In the cover image, an electron micrograph of an Atgl-KO/cTg club cell shows substantial lipid accumulation within the intracellular lipid droplets.
The transcription factor Signal transducer and activator of transcription 1 (STAT1) plays a critical role in modulating the differentiation of CD4+ T cells producing IL-17 and GM-CSF, which promote the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The protective role of STAT1 in MS and EAE has been largely attributed to its ability to limit pathogenic T helper (Th) cells and promote regulatory T (Treg) cells. Using mice with selective deletion of STAT1 in T cells (STAT1CD4-Cre), we identify a novel mechanism by which STAT1 regulates neuroinflammation independently of Foxp3+ Treg cells. STAT1-deficient effector T cells become the target of NK cell-mediated killing, limiting their capacity to induce EAE. STAT1-deficient T cells promoted their own killing by producing more IL-2 that in return activated NK cells. Elimination of NK cells restored EAE susceptibility in STAT1CD4-Cre mice. Therefore, our study suggests that the STAT1 pathway can be manipulated to limit autoreactive T cells during autoimmunity directed against the central nervous system.
Carlos A. Arbelaez, Pushpalatha Palle, Jonathan Charaix, Estelle Bettelli
The Aedes aegypti mosquito transmits both dengue (DENV) and Zika (ZIKV) viruses. Individuals in endemic areas are at risk for infection with both viruses as well as repeated DENV infection. In the presence of anti-DENV antibodies, outcomes of secondary DENV infection range from mild to life-threatening. Further, the role of cross-reactive antibodies on the course of ZIKV infection remains unclear. We assessed the ability of cross-reactive DENV monoclonal antibodies or polyclonal immunoglobulin isolated after DENV vaccination to upregulate type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) in response to both heterotypic DENV- and ZIKV- infected cells. We found a range in the ability of antibodies to increase pDC IFN production and a positive correlation between IFN production and the ability of an antibody to bind to the infected cell surface. Engagement of Fc receptors on the pDC and Fab binding of an epitope on infected cells was required to mediate increased IFN production by providing specificity to and promoting pDC sensing of DENV or ZIKV. This represents a mechanism independent of neutralization by which pre-existing cross-reactive DENV antibodies could protect a subset of individuals from severe outcomes during secondary heterotypic DENV or ZIKV infection.
Laura K. Aisenberg, Kimberly E. Rousseau, Katherine Cascino, Guido Massaccesi, William H. Aisenberg, Wensheng Luo, Kar Muthumani, David B. Weiner, Stephen S. Whitehead, Michael A. Chattergoon, Anna P. Durbin, Andrea L. Cox
Macrophages play a crucial role in the inflammatory response to the human stomach pathogen Helicobacter pylori, which infects half of the world’s population and causes gastric cancer. Recent studies have highlighted the importance of macrophage immunometabolism in their activation state and function. We have demonstrated that the cysteine-producing enzyme, cystathionine g-lyase (CTH), is upregulated in humans and mice with H. pylori infection. Here we show that induction of CTH in macrophages by H. pylori promotes persistent inflammation. Cth–/– mice have reduced macrophage and T-cell activation in H. pylori-infected tissues, an altered metabolome, and decreased enrichment of immune-associated gene networks, culminating in decreased H. pylori-induced-gastritis. CTH is downstream of the proposed anti-inflammatory molecule, S-adenosylmethionine (SAM). While Cth–/– mice exhibit gastric SAM accumulation, WT mice treated with SAM did not display protection against H. pylori-induced inflammation. Instead, we demonstrate that Cth-deficient macrophages exhibit alterations in the proteome, decreased NF-kB activation, diminished expression of macrophage activation markers, and impaired oxidative phosphorylation and glycolysis. Thus, through altering cellular respiration, CTH is a key enhancer of macrophage activation contributing to a pathogenic inflammatory response that is the universal precursor for the development of H. pylori-induced gastric disease.
Yvonne L. Latour, Johanna C. Sierra, Jordan L. Finley, Mohammad Asim, Daniel P. Barry, Margaret M. Allaman, Thaddeus M. Smith, Kara M. McNamara, Paula B. Luis, Claus Schneider, Justin Jacobse, Jeremy A. Goettel, M. Wade Calcutt, Kristie L. Rose, Kevin L Schey, Ginger L. Milne, Alberto G. Delgado, M. Blanca Piazuelo, Bindu D. Paul, Solomon Snyder, Alain P. Gobert, Keith T. Wilson
Cyclophosphamide (CPA) and doxorubicin (DOX) are key components of chemotherapy for triple-negative breast cancer (TNBC) although suboptimal outcomes are commonly associated with drug resistance and/or intolerable side-effects. Through an approach combining high-throughput screening and chemical modification, we developed CN06 as a dual activator of the constitutive androstane receptor (CAR) and nuclear factor erythroid 2-related factor 2 (Nrf2). CN06 enhances CAR-induced bioactivation of CPA (a prodrug) by provoking hepatic expression of CYP2B6, while repressing DOX-induced cytotoxicity in cardiomyocytes in vitro via stimulating Nrf2-antioxidant signaling. Utilizing a multicellular co-culture model incorporating human primary hepatocytes, TNBC cells, and cardiomyocytes, we show that CN06 increased CPA/DOX-mediated TNBC cell death via CAR-dependent CYP2B6 induction and subsequent conversion of CPA to its active metabolite 4-hydroxy-CPA, while protecting against DOX-induced cardiotoxicity by selectively activating Nrf2-antioxidant signaling in cardiomyocytes but not in TNBC cells. Further, CN06 preserves the viability and function of human iPSC-derived cardiomyocytes by modulating antioxidant defenses, decreasing apoptosis, and enhancing the kinetics of contraction and relaxation. Collectively, our findings identify CAR and Nrf2 as novel combined therapeutic targets whereby CN06 holds the potential to improve the efficacy:toxicity ratio of CPA/DOX-containing chemotherapy.
Sydney Stern, Dongdong Liang, Linhao Li, Ritika Kurian, Caitlin Lynch, Srilatha Sakamuru, Scott Heyward, Junran Zhang, Kafayat Ajoke Kareem, Young Wook Chun, Ruili Huang, Menghang Xia, Charles C. Hong, Fengtian Xue, Hongbing Wang
BACKGROUND. Sudden cardiac death (SCD) remains a worldwide public health problem in need of better noninvasive predictive tools. Current guidelines for primary preventive SCD therapies such as implantable cardioverter defibrillators (ICDs) are based on left ventricular ejection fraction (LVEF), but these are imprecise with fewer than 5% of ICDs delivering life-saving therapy per year. Impaired cardiac metabolism and ATP depletion cause arrhythmias in experimental models, but a link between arrhythmias and cardiac energetic abnormalities in people has not been explored, nor the potential for metabolically predicting clinical SCD risk. METHODS. We prospectively measured myocardial energy metabolism noninvasively with phosphorus magnetic resonance spectroscopy in patients with no history of significant arrhythmias prior to scheduled ICD implantation for primary prevention in the setting of reduced LVEF (≤35%). RESULTS. By two different analyses, low myocardial ATP significantly predicted the composite of subsequent appropriate ICD firings for life-threatening arrhythmias and cardiac death over ~10 years. Life-threatening arrhythmia risk was ~3-fold higher in low ATP patients and independent of established risk factors including LVEF. In patients with normal ATP, rates of appropriate ICD firings were several-fold lower than reported rates of ICD complications and inappropriate firings. CONCLUSION. These first data linking in vivo myocardial ATP depletion and subsequent significant arrhythmic events in people suggest an energetic component to clinical life-threatening ventricular arrhythmogenesis. The findings support investigation of metabolic strategies that limit ATP loss to treat or prevent life-threatening cardiac arrhythmias and herald non-invasive metabolic imaging as a complementary SCD risk stratification tool. TRIAL REGISTRATION. NCT00181233. FUNDING. This work was supported by DW Reynolds Foundation, the National Institutes of Health (grants HL61912, HL056882, HL103812, HL132181, HL140034), and the Russell H. Morgan (P.A.B.) and Clarence Doodeman (R.G.W.) Endowments at Johns Hopkins.
T. Jake Samuel, Shenghan Lai, Michael Schär, Katherine C. Wu, Angela M. Steinberg, An-Chi Wei, Mark Anderson, Gordon F. Tomaselli, Gary Gerstenblith, Paul A. Bottomley, Robert G. Weiss