Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration.

Abstract:

:Retinitis pigmentosa, caused predominantly by mutations in photoreceptor genes, currently lacks comprehensive treatment. We discover that retinal microglia contribute non-cell autonomously to rod photoreceptor degeneration by primary phagocytosis of living rods. Using rd10 mice, we found that the initiation of rod degeneration is accompanied by early infiltration of microglia, upregulation of phagocytic molecules in microglia, and presentation of "eat-me" signals on mutated rods. On live-cell imaging, infiltrating microglia interact dynamically with photoreceptors via motile processes and engage in rapid phagocytic engulfment of non-apoptotic rods. Microglial contribution to rod demise is evidenced by morphological and functional amelioration of photoreceptor degeneration following genetic ablation of retinal microglia. Molecular inhibition of microglial phagocytosis using the vitronectin receptor antagonist cRGD also improved morphological and functional parameters of degeneration. Our findings highlight primary microglial phagocytosis as a contributing mechanism underlying cell death in retinitis pigmentosa and implicate microglia as a potential cellular target for therapy.

journal_name

EMBO Mol Med

journal_title

EMBO molecular medicine

authors

Zhao L,Zabel MK,Wang X,Ma W,Shah P,Fariss RN,Qian H,Parkhurst CN,Gan WB,Wong WT

doi

10.15252/emmm.201505298

subject

Has Abstract

pub_date

2015-09-01 00:00:00

pages

1179-97

issue

9

eissn

1757-4676

issn

1757-4684

pii

emmm.201505298

journal_volume

7

pub_type

杂志文章
  • Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia.

    abstract::Initiating neoplastic cell transformation events are of paramount importance for the comprehension of regeneration and vanguard oncogenic processes but are difficult to characterize and frequently clinically overlooked. In epithelia, pre-neoplastic transformation stages are often distinguished by the appearance of phe...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章,评审

    doi:10.1002/emmm.201302834

    authors: Regalo G,Leutz A

    更新日期:2013-08-01 00:00:00

  • Compounds producing an effective combinatorial regimen for disruption of HIV-1 latency.

    abstract::Highly active antiretroviral therapy (HAART) has improved the outlook for the HIV epidemic, but does not provide a cure. The proposed "shock-and-kill" strategy is directed at inducing latent HIV reservoirs, which may then be purged via boosted immune response or targeting infected cells. We describe five novel compoun...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201708193

    authors: Hashemi P,Barreto K,Bernhard W,Lomness A,Honson N,Pfeifer TA,Harrigan PR,Sadowski I

    更新日期:2018-02-01 00:00:00

  • Metronomic chemotherapy offsets HIFα induction upon maximum-tolerated dose in metastatic cancers.

    abstract::Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptiona...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201911416

    authors: Schito L,Rey S,Xu P,Man S,Cruz-Muñoz W,Kerbel RS

    更新日期:2020-09-07 00:00:00

  • Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing.

    abstract::In the normal quiescent vasculature, only 0.01% of endothelial cells (ECs) are proliferating. However, this proportion increases dramatically following the angiogenic switch during tumor growth or wound healing. Recent evidence suggests that this angiogenic switch is accompanied by a metabolic switch. Here, we show th...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.201303016

    authors: Coutelle O,Hornig-Do HT,Witt A,Andree M,Schiffmann LM,Piekarek M,Brinkmann K,Seeger JM,Liwschitz M,Miwa S,Hallek M,Krönke M,Trifunovic A,Eming SA,Wiesner RJ,Hacker UT,Kashkar H

    更新日期:2014-05-01 00:00:00

  • VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption.

    abstract::Vascular endothelial growth factor C (VEGF-C) binding to its tyrosine kinase receptor VEGFR-3 drives lymphatic vessel growth during development and in pathological processes. Although the VEGF-C/VEGFR-3 pathway provides a target for treatment of cancer and lymphedema, the physiological functions of VEGF-C in adult vas...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201505731

    authors: Nurmi H,Saharinen P,Zarkada G,Zheng W,Robciuc MR,Alitalo K

    更新日期:2015-11-01 00:00:00

  • Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers.

    abstract::Mitochondrial disorders (MDs) are inherited multi-organ diseases with variable phenotypes. Inclusion body myositis (IBM), a sporadic inflammatory muscle disease, also shows mitochondrial dysfunction. We investigated whether primary and secondary MDs modify metabolism to reveal pathogenic pathways and biomarkers. We in...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201809091

    authors: Buzkova J,Nikkanen J,Ahola S,Hakonen AH,Sevastianova K,Hovinen T,Yki-Järvinen H,Pietiläinen KH,Lönnqvist T,Velagapudi V,Carroll CJ,Suomalainen A

    更新日期:2018-12-01 00:00:00

  • Culturing human intestinal stem cells for regenerative applications in the treatment of inflammatory bowel disease.

    abstract::Both the incidence and prevalence of inflammatory bowel disease (IBD) is increasing globally; in the industrialized world up to 0.5% of the population are affected and around 4.2 million individuals suffer from IBD in Europe and North America combined. Successful engraftment in experimental colitis models suggests tha...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章,评审

    doi:10.15252/emmm.201607260

    authors: Holmberg FE,Seidelin JB,Yin X,Mead BE,Tong Z,Li Y,Karp JM,Nielsen OH

    更新日期:2017-05-01 00:00:00

  • Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity.

    abstract::Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. ...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201708485

    authors: Alsina-Beauchamp D,Escós A,Fajardo P,González-Romero D,Díaz-Mora E,Risco A,Martín-Serrano MA,Del Fresno C,Dominguez-Andrés J,Aparicio N,Zur R,Shpiro N,Brown GD,Ardavín C,Netea MG,Alemany S,Sanz-Ezquerro JJ,Cuenda A

    更新日期:2018-05-01 00:00:00

  • A novel thermoregulatory role for PDE10A in mouse and human adipocytes.

    abstract::Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small-animal PET/MRI and the nove...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201506085

    authors: Hankir MK,Kranz M,Gnad T,Weiner J,Wagner S,Deuther-Conrad W,Bronisch F,Steinhoff K,Luthardt J,Klöting N,Hesse S,Seibyl JP,Sabri O,Heiker JT,Blüher M,Pfeifer A,Brust P,Fenske WK

    更新日期:2016-07-01 00:00:00

  • Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling.

    abstract::Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms r...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201911739

    authors: Bosakova M,Abraham SP,Nita A,Hruba E,Buchtova M,Taylor SP,Duran I,Martin J,Svozilova K,Barta T,Varecha M,Balek L,Kohoutek J,Radaszkiewicz T,Pusapati GV,Bryja V,Rush ET,Thiffault I,Nickerson DA,Bamshad MJ,Universit

    更新日期:2020-11-06 00:00:00

  • SIL1, a causative cochaperone gene of Marinesco-Söjgren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex.

    abstract::Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessively inherited disorder with mental retardation (MR). Recently, mutations in the SIL1 gene, encoding a co-chaperone which regulates the chaperone HSPA5, were identified as a major cause of MSS. We here examined the pathophysiological significance of SIL1 muta...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.201303069

    authors: Inaguma Y,Hamada N,Tabata H,Iwamoto I,Mizuno M,Nishimura YV,Ito H,Morishita R,Suzuki M,Ohno K,Kumagai T,Nagata K

    更新日期:2014-03-01 00:00:00

  • Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers.

    abstract::Germ-line mutations in the BRCA1 gene strongly predispose women to breast cancer (lifetime risk up to 80%). Furthermore, the BRCA1 protein is absent or present at very low levels in about one third of sporadic breast cancers. However, the mechanisms underlying BRCA1 somatic inactivation appear multiple and are still n...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.201100136

    authors: Garcia AI,Buisson M,Bertrand P,Rimokh R,Rouleau E,Lopez BS,Lidereau R,Mikaélian I,Mazoyer S

    更新日期:2011-05-01 00:00:00

  • iPhemap: an atlas of phenotype to genotype relationships of human iPSC models of neurological diseases.

    abstract::Disease modeling with induced pluripotent stem cells (iPSCs) is creating an abundance of phenotypic information that has become difficult to follow and interpret. Here, we report a systematic analysis of research practices and reporting bias in neurological disease models from 93 published articles. We find heterogene...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201708191

    authors: Hollingsworth EW,Vaughn JE,Orack JC,Skinner C,Khouri J,Lizarraga SB,Hester ME,Watanabe F,Kosik KS,Imitola J

    更新日期:2017-12-01 00:00:00

  • Somatically mutated ABL1 is an actionable and essential NSCLC survival gene.

    abstract::The lack of actionable mutations in patients with non-small cell lung cancer (NSCLC) presents a significant hurdle in the design of targeted therapies for this disease. Here, we identify somatically mutated ABL1 as a genetic dependency that is required to maintain NSCLC cell survival. We demonstrate that NSCLC cells w...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201505456

    authors: Testoni E,Stephenson NL,Torres-Ayuso P,Marusiak AA,Trotter EW,Hudson A,Hodgkinson CL,Morrow CJ,Dive C,Brognard J

    更新日期:2016-02-01 00:00:00

  • Salvaging hope: Is increasing NAD(+) a key to treating mitochondrial myopathy?

    abstract::Mitochondrial diseases can arise from mutations either in mitochondrial DNA or in nuclear DNA encoding mitochondrially destined proteins. Currently, there is no cure for these diseases although treatments to ameliorate a subset of the symptoms are being developed. In this issue of EMBO Molecular Medicine, Khan et al (...

    journal_title:EMBO molecular medicine

    pub_type: 评论,杂志文章

    doi:10.15252/emmm.201404179

    authors: Lightowlers RN,Chrzanowska-Lightowlers ZM

    更新日期:2014-06-01 00:00:00

  • Quantitative tracking of T cell clones after haematopoietic stem cell transplantation.

    abstract::Autologous haematopoietic stem cell transplantation is highly efficient for the treatment of systemic autoimmune diseases, but its consequences for the immune system remain poorly understood. Here, we describe an optimized RNA-based technology for unbiased amplification of T cell receptor beta-chain libraries and use ...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.201100129

    authors: Mamedov IZ,Britanova OV,Bolotin DA,Chkalina AV,Staroverov DB,Zvyagin IV,Kotlobay AA,Turchaninova MA,Fedorenko DA,Novik AA,Sharonov GV,Lukyanov S,Chudakov DM,Lebedev YB

    更新日期:2011-04-01 00:00:00

  • Transparency and accountability.

    abstract::EMBO Molecular Medicine is enriched by a number of innovative policies designed to enhance the editorial process: peer review process files, de-emphasis of confidential referee comments and cross-refereeing. ...

    journal_title:EMBO molecular medicine

    pub_type: 社论

    doi:10.1002/emmm.201000094

    authors: Pulverer B

    更新日期:2010-09-01 00:00:00

  • Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K.

    abstract::The tumor suppressors Pten and p53 are frequently lost in breast cancer, yet the consequences of their combined inactivation are poorly understood. Here, we show that mammary-specific deletion of Pten via WAP-Cre, which targets alveolar progenitors, induced tumors with shortened latency compared to those induced by MM...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201404402

    authors: Liu JC,Voisin V,Wang S,Wang DY,Jones RA,Datti A,Uehling D,Al-awar R,Egan SE,Bader GD,Tsao M,Mak TW,Zacksenhaus E

    更新日期:2014-12-01 00:00:00

  • Pathogens under scrutiny in the south of France.

    abstract::The first EMBO workshop on Emerging Themes in Infection Biology was held last June in the South of France. It gathered scientists working on various pathogens from viruses and bacteria to larger eukaryotic fungi and parasites. Topics included not only the crosstalk between pathogens and their hosts but also the tools ...

    journal_title:EMBO molecular medicine

    pub_type:

    doi:10.1002/emmm.201000087

    authors: Caldeira S,Dumenil G

    更新日期:2010-09-01 00:00:00

  • WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer.

    abstract::Wnt/β-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of β-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally a...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.201201320

    authors: Wend P,Runke S,Wend K,Anchondo B,Yesayan M,Jardon M,Hardie N,Loddenkemper C,Ulasov I,Lesniak MS,Wolsky R,Bentolila LA,Grant SG,Elashoff D,Lehr S,Latimer JJ,Bose S,Sattar H,Krum SA,Miranda-Carboni GA

    更新日期:2013-02-01 00:00:00

  • Systemic CD4 immunity: A powerful clinical biomarker for PD-L1/PD-1 immunotherapy.

    abstract::The search for non-invasive systemic biomarkers of response to PD-L1/PD-1 blockade immunotherapy is currently a priority in oncoimmunology. In contrast to classical tumor biomarkers, the identification of clinically useful immunological biomarkers is certainly a challenge, as anti-cancer immune responses depend on the...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.202012706

    authors: Zuazo M,Arasanz H,Bocanegra A,Chocarro L,Vera R,Escors D,Kagamu H,Kochan G

    更新日期:2020-09-07 00:00:00

  • Dissecting human antibody responses: useful, basic and surprising findings.

    abstract::Human memory B cells and plasma cells represent a rich source of antibodies that have been selected in response to human pathogens. In the last decade, different methods have been developed to interrogate the human memory repertoire and isolate monoclonal antibodies. I will discuss how a target-agnostic approach based...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201808879

    authors: Lanzavecchia A

    更新日期:2018-03-01 00:00:00

  • MicroRNA-483 amelioration of experimental pulmonary hypertension.

    abstract::Endothelial dysfunction is critically involved in the pathogenesis of pulmonary arterial hypertension (PAH) and that exogenously administered microRNA may be of therapeutic benefit. Lower levels of miR-483 were found in serum from patients with idiopathic pulmonary arterial hypertension (IPAH), particularly those with...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201911303

    authors: Zhang J,He Y,Yan X,Chen S,He M,Lei Y,Zhang J,Gongol B,Gu M,Miao Y,Bai L,Cui X,Wang X,Zhang Y,Fan F,Li Z,Shen Y,Chou CH,Huang HD,Malhotra A,Rabinovitch M,Jing ZC,Shyy JY

    更新日期:2020-05-08 00:00:00

  • Effective gene therapy for haemophilic mice with pathogenic factor IX antibodies.

    abstract::Formation of pathogenic antibodies is a major problem in replacement therapies for inherited protein deficiencies. For example, antibodies to coagulation factors ('inhibitors') seriously complicate treatment of haemophilia. While immune tolerance induction (ITI) protocols have been developed, inhibitors against factor...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.201302859

    authors: Markusic DM,Hoffman BE,Perrin GQ,Nayak S,Wang X,LoDuca PA,High KA,Herzog RW

    更新日期:2013-11-01 00:00:00

  • Inducing mitophagy in diabetic platelets protects against severe oxidative stress.

    abstract::Diabetes mellitus (DM) is a growing international concern. Considerable mortality and morbidity associated with diabetes mellitus arise predominantly from thrombotic cardiovascular events. Oxidative stress-mediated mitochondrial damage contributes significantly to enhanced thrombosis in DM A basal autophagy process ha...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201506046

    authors: Lee SH,Du J,Stitham J,Atteya G,Lee S,Xiang Y,Wang D,Jin Y,Leslie KL,Spollett G,Srivastava A,Mannam P,Ostriker A,Martin KA,Tang WH,Hwa J

    更新日期:2016-07-01 00:00:00

  • Adeno-associated virus-vectored influenza vaccine elicits neutralizing and Fcγ receptor-activating antibodies.

    abstract::The current seasonal inactivated influenza vaccine protects only against a narrow range of virus strains as it triggers a dominant antibody response toward the hypervariable hemagglutinin (HA) head region. The discovery of rare broadly protective antibodies against conserved regions in influenza virus proteins has pro...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201910938

    authors: Demminger DE,Walz L,Dietert K,Hoffmann H,Planz O,Gruber AD,von Messling V,Wolff T

    更新日期:2020-05-08 00:00:00

  • Targeting cardiac hypertrophy through a nuclear co-repressor.

    abstract::Heart failure entails the inability of the heart to pump blood to vital organs. One of the main risk factors for heart failure is the development of pathological hypertrophy. In this issue of EMBO Molecular Medicine, Li and coworkers show that NCoR1, a co-repressor of transcription factors, inhibits the transcriptiona...

    journal_title:EMBO molecular medicine

    pub_type: 评论,杂志文章

    doi:10.15252/emmm.201911297

    authors: Grund A,Heineke J

    更新日期:2019-11-07 00:00:00

  • Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome.

    abstract::Fetal alcohol spectrum disorder (FASD) is a frequent cause of mental retardation. However, the molecular mechanisms underlying brain development defects induced by maternal alcohol consumption during pregnancy are unclear. We used normal and Hsf2-deficient mice and cell systems to uncover a pivotal role for heat shock...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201303311

    authors: El Fatimy R,Miozzo F,Le Mouël A,Abane R,Schwendimann L,Sabéran-Djoneidi D,de Thonel A,Massaoudi I,Paslaru L,Hashimoto-Torii K,Christians E,Rakic P,Gressens P,Mezger V

    更新日期:2014-08-01 00:00:00

  • Chimeric Pneumoviridae fusion proteins as immunogens to induce cross-neutralizing antibody responses.

    abstract::Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV), two members of the Pneumoviridae family, account for the majority of severe lower respiratory tract infections worldwide in very young children. They are also a frequent cause of morbidity and mortality in the elderly and immunocompromised adul...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201708078

    authors: Olmedillas E,Cano O,Martínez I,Luque D,Terrón MC,McLellan JS,Melero JA,Más V

    更新日期:2018-02-01 00:00:00

  • A surrogate marker for Abeta42 production in the CNS.

    abstract::Alzheimer's disease (AD) is the most common cause of dementia. There are currently no effective treatments that may delay the onset, slow the progression or prevent the disease. Unless such treatments are developed, the number of AD cases is expected to double in the next 30 years. There is overwhelming genetic and bi...

    journal_title:EMBO molecular medicine

    pub_type: 评论,杂志文章

    doi:10.1002/emmm.200900030

    authors: Holtzman DM

    更新日期:2009-07-01 00:00:00