Recently published - More

Abstract

Atherosclerosis is a chronic inflammatory disease of the vasculature that is initiated by cholesterol deposition into the arterial wall, which triggers the infiltration of immune and inflammatory cells, including monocytes and macrophages. As atherosclerotic plaques progress, localized hypoxia promotes compensatory angiogenesis from the vasa vasorum. Immature neovessels are prone to leakage, thus destabilizing the plaque and leading to intraplaque hemorrhage. Macrophages with different phenotypes, ranging from classical inflammatory subtypes to alternatively activated antiinflammatory macrophages, have been identified in atherosclerotic lesions. Antiinflammatory hemoglobin-scavenging CD163+ macrophages are present in neovessel- and hemorrhage-rich areas; however, the role of these macrophages in atherogenesis has been unclear. In this issue of the JCI, Guo, Akahori, and colleagues show that CD163+ macrophages promote angiogenesis, vessel permeability, and leucocyte infiltration in human and mouse atherosclerotic lesions through a mechanism involving hemoglobin:haptoglobin/CD163/HIF1α-mediated VEGF induction. This study thus identifies proatherogenic properties of CD163+ macrophages, which previously were thought to be beneficial.

Authors

Benoit Pourcet, Bart Staels

×

Abstract

Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non–foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.

Authors

Liang Guo, Hirokuni Akahori, Emanuel Harari, Samantha L. Smith, Rohini Polavarapu, Vinit Karmali, Fumiyuki Otsuka, Rachel L. Gannon, Ryan E. Braumann, Megan H. Dickinson, Anuj Gupta, Audrey L. Jenkins, Michael J. Lipinski, Johoon Kim, Peter Chhour, Paul S. de Vries, Hiroyuki Jinnouchi, Robert Kutys, Hiroyoshi Mori, Matthew D. Kutyna, Sho Torii, Atsushi Sakamoto, Cheol Ung Choi, Qi Cheng, Megan L. Grove, Mariem A. Sawan, Yin Zhang, Yihai Cao, Frank D. Kolodgie, David P. Cormode, Dan E. Arking, Eric Boerwinkle, Alanna C. Morrison, Jeanette Erdmann, Nona Sotoodehnia, Renu Virmani, Aloke V. Finn

×

Abstract

SCN5A encodes the voltage-gated Na+ channel NaV1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure–related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. We recently generated a transcriptome-wide map of microRNA (miR) binding sites in human heart, evaluated their overlap with common SNPs, and identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within the SCN5A coding sequence. This SNP was previously shown to reproducibly associate with cardiac electrophysiological parameters, but was not considered to be causal. Here, we show that miR-24 potently suppresses SCN5A expression and that rs1805126 modulates this regulation. We found that the rs1805126 minor allele associates with decreased cardiac SCN5A expression and that heart failure subjects homozygous for the minor allele have decreased ejection fraction and increased mortality, but not increased ventricular tachyarrhythmias. In mice, we identified a potential basis for this in discovering that decreased Scn5a expression leads to accumulation of myocardial reactive oxygen species. Together, these data reiterate the importance of considering the mechanistic significance of synonymous SNPs as they relate to miRs and disease, and highlight a surprising link between SCN5A expression and nonarrhythmic death in heart failure.

Authors

Xiaoming Zhang, Jin-Young Yoon, Michael Morley, Jared M. McLendon, Kranti A. Mapuskar, Rebecca Gutmann, Haider Mehdi, Heather L. Bloom, Samuel C. Dudley, Patrick T. Ellinor, Alaa A. Shalaby, Raul Weiss, W.H. Wilson Tang, Christine S. Moravec, Madhurmeet Singh, Anne L. Taylor, Clyde W. Yancy, Arthur M. Feldman, Dennis M. McNamara, Kaikobad Irani, Douglas R. Spitz, Patrick Breheny, Kenneth B. Margulies, Barry London, Ryan L. Boudreau

×

Abstract

Pro-opiomelanocortin (POMC) neurons function as key regulators of metabolism and physiology by releasing prohormone-derived neuropeptides with distinct biological activities. However, our understanding of early events in prohormone maturation in the ER remains incomplete. Highlighting the significance of this gap in knowledge, a single POMC cysteine-to-phenylalanine mutation at position 28 (POMC-C28F) is defective for ER processing and causes early onset obesity in a dominant-negative manner in humans through an unclear mechanism. Here, we report a pathologically important role of Sel1L-Hrd1, the protein complex of ER-associated degradation (ERAD), within POMC neurons. Mice with POMC neuron–specific Sel1L deficiency developed age-associated obesity due, at least in part, to the ER retention of POMC that led to hyperphagia. The Sel1L-Hrd1 complex targets a fraction of nascent POMC molecules for ubiquitination and proteasomal degradation, preventing accumulation of misfolded and aggregated POMC, thereby ensuring that another fraction of POMC can undergo normal posttranslational processing and trafficking for secretion. Moreover, we found that the disease-associated POMC-C28F mutant evades ERAD and becomes aggregated due to the presence of a highly reactive unpaired cysteine thiol at position 50. Thus, this study not only identifies ERAD as an important mechanism regulating POMC maturation within the ER, but also provides insights into the pathogenesis of monogenic obesity associated with defective prohormone folding.

Authors

Geun Hyang Kim, Guojun Shi, Diane R.M. Somlo, Leena Haataja, Soobin Song, Qiaoming Long, Eduardo A. Nillni, Malcolm J. Low, Peter Arvan, Martin G. Myers Jr., Ling Qi

×

Abstract

Multisystem proteinopathy (MSP) involves disturbances of stress granule (SG) dynamics and autophagic protein degradation that underlie the pathogenesis of a spectrum of degenerative diseases that affect muscle, brain, and bone. Specifically, identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes: amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Paget’s disease of the bone, and distal myopathy. It has been hypothesized that clinical pleiotropy relates to additional genetic determinants, but thus far, evidence has been lacking. Here, we provide evidence that a TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 mutation. Experimentally, the TIA1-N357S variant significantly enhances liquid-liquid–phase separation in vitro and impairs SG dynamics in living cells. Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly impairs SG dynamics. TIA1-N357S–persistent SGs have increased association with SQSTM1, accumulation of ubiquitin conjugates, and additional aggregated proteins. Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X mutation in myoblasts leads to impaired SG clearance and myotoxicity relative to control myoblasts. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin-mediated autophagic degradation that drives the penetrance of an MSP phenotype.

Authors

YouJin Lee, Per Harald Jonson, Jaakko Sarparanta, Johanna Palmio, Mohona Sarkar, Anna Vihola, Anni Evilä, Tiina Suominen, Sini Penttilä, Marco Savarese, Mridul Johari, Marie-Christine Minot, David Hilton-Jones, Paul Maddison, Patrick Chinnery, Jens Reimann, Cornelia Kornblum, Torsten Kraya, Stephan Zierz, Carolyn Sue, Hans Goebel, Asim Azfer, Stuart H. Ralston, Peter Hackman, Robert C. Bucelli, J. Paul Taylor, Conrad C. Weihl, Bjarne Udd

×

Abstract

The compensatory proliferation of insulin-producing β cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of β cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between β cell compensation and lipid metabolism upon obesity and peripheral insulin resistance, we eliminated LDL receptor–related protein 1 (LRP1), a pleiotropic mediator of cholesterol, insulin, energy metabolism, and other cellular processes, in β cells. Upon high-fat diet exposure, LRP1 ablation significantly impaired insulin secretion and proliferation of β cells. The diminished insulin signaling was partly contributed to by the hypersensitivity to glucose-induced, Ca2+-dependent activation of Erk and the mTORC1 effector p85 S6K1. Surprisingly, in LRP1-deficient islets, lipotoxic sphingolipids were mitigated by improved lipid metabolism, mediated at least in part by the master transcriptional regulator PPARγ2. Acute overexpression of PPARγ2 in β cells impaired insulin signaling and insulin secretion. Elimination of Apbb2, a functional regulator of LRP1 cytoplasmic domain, also impaired β cell function in a similar fashion. In summary, our results uncover the double-edged effects of intracellular lipid metabolism on β cell function and viability in obesity and type 2 diabetes and highlight LRP1 as an essential regulator of these processes.

Authors

Risheng Ye, Ruth Gordillo, Mengle Shao, Toshiharu Onodera, Zhe Chen, Shiuhwei Chen, Xiaoli Lin, Jeffrey A. SoRelle, Xiaohong Li, Miao Tang, Mark P. Keller, Regina Kuliawat, Alan D. Attie, Rana K. Gupta, William L. Holland, Bruce Beutler, Joachim Herz, Philipp E. Scherer

×

Abstract

Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA–producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2). This reprogrammed the local chromatin at the HIV LTR through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminished histone crotonylation–induced HIV replication and reactivation. ACSS2 induction was highly synergistic in combination with either a protein kinase C agonist (PEP005) or a histone deacetylase inhibitor (vorinostat) in reactivating latent HIV. In the SIV-infected nonhuman primate model of AIDS, the expression of ACSS2 was significantly induced in intestinal mucosa in vivo, which correlated with altered fatty acid metabolism. Our study links the HIV/SIV infection–induced fatty acid enzyme ACSS2 to HIV latency and identifies histone lysine crotonylation as a novel epigenetic regulator for HIV transcription that can be targeted for HIV eradication.

Authors

Guochun Jiang, Don Nguyen, Nancie M. Archin, Steven A. Yukl, Gema Méndez-Lagares, Yuyang Tang, Maher M. Elsheikh, George R. Thompson III, Dennis J. Hartigan-O’Connor, David M. Margolis, Joseph K. Wong, Satya Dandekar

×

Abstract

Heart failure (HF) has been referred to as the cardiovascular epidemic of our time. Understanding the molecular determinants of HF disease progression and mortality risk is of utmost importance. In this issue of the JCI, Zhang et al. uncover an important link between clinical HF mortality risk and a common variant that regulates SCN5A expression through microRNA-dependent (miR-dependent)mechanisms. They also demonstrate that haploinsufficiency of SCN5A is associated with increased accumulation of reactive oxygen species (ROS) in a genetically engineered murine model. Their data suggest that even modest depression of SCN5A expression may promote pathologic cardiac remodeling and progression of HF.

Authors

David S. Park, Glenn I. Fishman

×

In-Press Preview - More

Abstract

The discovery of an HIV-1 cure remains a medical challenge because the virus rebounds quickly after the cessation of combination antiretroviral drug therapy (cART). Here, we investigate the potential of an engineered tandem bi-specific broadly neutralizing antibody (bs-bnAb) as an innovative product for HIV-1 prophylactic and therapeutic interventions. We discovered that by preserving two scFv binding domains of each parental bnAb, a single-gene-encoded tandem bs-bnAb, namely BiIA-SG, displayed significantly improved breadth and potency. BiIA-SG neutralized all 124 HIV-1 pseudotyped viruses tested, including global subtypes/recombinant forms, transmitted/founder viruses, and variants less or not susceptible to parental and many bnAbs, with an average IC50 value of 0.073 µ/ml (range < 0.001 to 1.03 µg/ml). In humanized mice, an injection of BiIA-SG conferred sterile protection when administered prior to challenges with diverse live HIV-1 stains. Moreover, while BiIA-SG delayed viral rebound in a short-term therapeutic setting when combined with cART, a single injection of AAV-transferred BiIA-SG gene resulted dose-dependently in prolonged in vivo expression of BiIA-SG, which was associated with complete viremia control and subsequent elimination of infected cells in humanized mice. These results warrant the clinical development of BiIA-SG as a promising bs-bnAb-based biomedical intervention for prevention and treatment of HIV-1 infections.

Authors

Xilin Wu, Jia Guo, Mengyue Niu, Minghui An, Li Liu, Hui Wang, Xia Jin, Qi Zhang, Ka Shing Lam, Tongjin Wu, Hua Wang, Qian Wang, Yanhua Du, Jingjing Li, Lin Cheng, Hang Ying Tang, Hong Shang, Linqi Zhang, Paul Zhou, Zhiwei Chen

×

Abstract

The immune system is tightly controlled by regulatory processes that allow for the elimination of invading pathogens, while limiting immunopathological damage to the host. In the present study, we found that conditional deletion of the cell surface receptor Toso on B cells unexpectedly resulted in impaired proinflammatory T cell responses, which led to impaired immune protection in an acute viral infection model, while, in a chronic inflammatory context, was associated with reduced immunopathological tissue damage. Toso exhibited its B cell-inherent immunoregulatory function by negatively controlling the pool of IL-10-competent B1 and B2 B cells, which were characterized by a high degree of self-reactivity and were shown to mediate immunosuppressive activity on inflammatory T cell responses in vivo. Our results indicate that Toso is involved in the differentiation/maintenance of regulatory B cells by fine-tuning B cell receptor (BCR)-activation thresholds. Furthermore, we showed that during influenza A-induced pulmonary inflammation the application of Toso-specific antibodies selectively induced IL-10-competent B cells at the site of inflammation and resulted in decreased proinflammatory cytokine production by lung T cells. These findings suggest that Toso may serve as a novel therapeutic target to dampen pathogenic T cell responses via the modulation of IL-10-competent regulatory B cells.

Authors

Jinbo Yu, Vu Huy Hoang Duong, Katrin Westphal, Andreas Westphal, Abdulhadi Suwandi, Guntram A. Grassl, Korbinian Brand, Andrew C. Chan, Niko Föger, Kyeong-Hee Lee

×

Abstract

The lack of defined correlates of protection hampers development of vaccines against tuberculosis (TB). In vitro mycobacterial outgrowth assays are thought to better capture the complexity of the human host/Mycobacterium tuberculosis (Mtb) interaction. We used a PBMC-based “mycobacterial-growth-inhibition-assay” (MGIA) to investigate the capacity to control outgrowth of Bacille Calmette-Guérin (BCG). Interestingly, strong control of BCG outgrowth was observed almost exclusively in individuals with recent exposure to Mtb, but not in (long-term) latent TB infection, and only modestly in BCG vaccinees. Mechanistically, control of mycobacterial outgrowth strongly correlated with the presence of a CD14dim monocyte population, but also required the presence of T cells. The nonclassical monocytes produced CXCL10, and CXCR3-receptor blockade inhibited the capacity to control BCG outgrowth. Expression of CXCR3 splice variants was altered in recently Mtb exposed individuals. Cytokines previously associated with trained immunity were detected in MGIA supernatants, and CXCL9, CXCL10, and CXCL11 represent new markers of trained immunity. These data indicate that CXCR3-ligands are associated with trained immunity and critical factors in controlling mycobacterial outgrowth.In conclusion, control of mycobacterial outgrowth early after exposure to Mtb is the result of trained immunity mediated by a CXCL10-producing non-classical CD14dim monocyte subset.

Authors

Simone A. Joosten, Krista E. van Meijgaarden, Sandra M. Arend, Corine Prins, Fredrik Oftung, Gro Ellen Korsvold, Sandra V. Kik, Rob J.W. Arts, Reinout van Crevel, Mihai G. Netea, Tom H.M. Ottenhoff

×

Abstract

HLA-B*57 control of HIV involves enhanced CD8+ T cell responses against infected cells, but extensive heterogeneity exists in level of HIV control among B*57+ individuals. Using whole genome sequencing of untreated B*57+ HIV-1 infected controllers and non-controllers, we identified a single variant (rs643347A/G) encoding an isoleucine to valine substitution at position 47 (I47V) of the inhibitory killer cell immunoglobulin-like receptor, KIR3DL1, as the only significant modifier of B*57 protection. The association replicated in an independent cohort and across multiple outcomes. The modifying effect of I47V was confined to B*57:01, and was not observed for the closely related B*57:03. Positions 2, 47, and 54 track one another nearly perfectly, and two KIR3DL1 allotypes differing only at these three positions showed significant differences in binding B*57:01 tetramers, where the protective allotype showed lower binding. Thus, variation in an immune natural killer cell receptor that binds B*57:01 modifies its protection. These data speak to exquisite specificity of KIR-HLA interactions in human health and disease.

Authors

Maureen P. Martin, Vivek Naranbhai, Patrick R. Shea, Ying Qi, Veron Ramsuran, Nicolas Vince, Xiaojiang Gao, Rasmi Thomas, Zabrina L. Brumme, Jonathan M. Carlson, Steven M. Wolinsky, James J. Goedert, Bruce D. Walker, Florencia P. Segal, Steven G. Deeks, David W. Haas, Stephen A. Migueles, Mark Connors, Nelson Michael, Jacques Fellay, Emma Gostick, Sian Llewellyn-Lacey, David A. Price, Bernard A. Lafont, Phillip Pymm, Philippa M. Saunders, Jacqueline Widjaja, Shu Cheng Wong, Julian P. Vivian, Jamie Rossjohn, Andrew G. Brooks, Mary Carrington

×

Abstract

BACKGROUND. Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited and multi-disciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS. To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimised analysis for detection of low mutant allele frequency. RESULTS. We discovered multiple mosaic activating variants in four genes of the RAS-MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germ-line RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterisation and two transgenic zebrafish AVM models which recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inihibitor, Vemurafinib, restored blood flow in AVM. CONCLUSIONS. Our findings uncover a major cause of sporadic vascular malformations of different clinical types, and thereby offer the potential of personalised medical treatment by repurposing existing licensed cancer therapies. FUNDING. This work was funded or supported by grants from AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, L’Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research (US).

Authors

Lara Al-Olabi, Satyamaanasa Polubothu, Katherine Dowsett, Katrina A. Andrews, Paulina Stadnik, Agnel P. Joseph, Rachel Knox, Alan Pittman, Graeme Clark, William Baird, Neil Bulstrode, Mary Glover, Kristiana Gordon, Darren Hargrave, Susan M. Huson, Thomas S. Jacques, Gregory James, Hannah Kondolf, Loshan Kangesu, Kim M. Keppler-Noreuil, Amjad Khan, Marjorie J. Lindhurst, Mark Lipson, Sahar Mansour, Justine O'Hara, Caroline Mahon, Anda Mosica, Celia Moss, Aditi Murthy, Juling Ong, Victoria E. Parker, Jean-Baptiste Rivière, Julie C. Sapp, Neil J. Sebire, Rahul Shah, Branavan Sivakumar, Anna Thomas, Alex Virasami, Regula Waelchli, Zhiqiang Zeng, Leslie G. Biesecker, Alex Barnacle, Maya Topf, Robert K. Semple, E. Elizabeth Patton, Veronica A. Kinsler

×

Advertisement

February 2018

128 2 cover

February 2018 Issue

On the cover:
Defective synaptic architecture in an infant epileptic disorder

This month’s cover features a cortical pyramidal neuron, distinguishable by its yellow nucleus. The interaction of FingR-gephyrin (green) and ankyrin (magenta) at the axion initial segment helps to stabilize inhibitory synapse organization. The cell is filled with red fluorescent protein for visualization. The corresponding study by Wang et al. describes the defective neuronal morphology, synaptogenesis, and inhibitory signaling that underlie early infantile epileptic encephalography 5, a disease linked to mutations in αII spectrin. Image credit: Yu Wang.

×
Jci tm 2018 02

February 2018 JCI This Month

JCI This Month is a digest of the research, reviews, and other features published each month.

×

Review Series - More

Fibrosis

Series edited by Dean Sheppard

Fibrosis describes a maladaptive response to injury that results in pathogenic production of extracellular matrix, the formation of stiff scar tissue, and compromised organ function. Although it is most often associated with chronic liver conditions and progressive lung disease, fibrosis can affect any organ of the body. There are few treatment options for this progressive, often fatal condition, but as ongoing research identifies the molecular pathways that initiate and propagate fibrotic remodeling, therapeutic possibilities may become available. The reviews in this series discuss recent insights into genetic predisposition to fibrotic disorders, the origins of fibroblasts and myofibroblasts, scar tissue formation, organ regeneration, and more, revealing opportunities to interrupt or even reverse disease progression.

×