The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Eva-maria Mandelkow - One of the best experts on this subject based on the ideXlab platform.
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microtubule affinity regulating kinase 2 mark2 turns on phosphatase and tensin homolog pten induced kinase 1 pink1 at thr 313 a mutation site in parkinson disease effects on mitochondrial transport
Journal of Biological Chemistry, 2012Co-Authors: Dorthe Matenia, Cindy Hempp, Annika Eikhof, Thomas Timm, Eva-maria MandelkowAbstract:The kinase MARK2/Par-1 plays key roles in several cell processes, including neurodegeneration such as Alzheimer disease by phosphorylating tau and detaching it from microtubules. In search of interaction partners of MARK2, we identified phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), which is important for the survival of neurons and whose mutations are linked to familial Parkinson disease (PD). MARK2 phosphorylated and activated the cleaved form of PINK1 (ΔN-PINK1; amino acids 156–581). Thr-313 was the primary phosphorylation site, a residue mutated to a non-phosphorylatable form (T313M) in a frequent variant of PD. Mutation of Thr-313 to Met or Glu in PINK1 showed toxic effects with abnormal mitochondrial distribution in neurons. MARK2 and PINK1 were found to colocalize with mitochondria and regulate their transport. ΔN-PINK1 promoted anterograde transport and increased the fraction of stationary mitochondria, whereas full-length PINK1 promoted retrograde transport. In both cases, MARK2 enhanced the effects. The results identify MARK2 as an upstream regulator of PINK1 and ΔN-PINK1 and provide insights into the regulation of mitochondrial trafficking in neurons and neurodegeneration in PD.
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accurate balance of the polarity kinase mark2 par 1 is required for proper cortical neuronal migration
The Journal of Neuroscience, 2008Co-Authors: Tamar Sapir, Thomas Timm, Eva-maria Mandelkow, Sivan Sapoznik, Talia Levy, Danit Finkelshtein, Anat Shmueli, Orly ReinerAbstract:Radial neuronal migration is key in structuring the layered cortex. Here we studied the role of MARK2/Par-1 in this process. The dual name stands for the MAP/microtubule affinity-regulating kinase 2 (MARK2) and the known polarity kinase 1 (Par-1). Reduced MARK2 levels using in utero electroporation resulted in multipolar neurons stalled at the intermediate zone border. Reintroduction of the wild-type kinase postmitotically improved neuronal migration. Our results indicated that reduction in MARK2 affected centrosomal dynamics in migrating neurons of the cerebral cortex. Increased MARK2 has been shown to destabilize microtubules, and here we show for the first time that reduced MARK2 stabilized microtubules in primary cultured neurons. Kinase-independent activity permitted multipolar-to-bipolar transition but did not restore proper migration. Increased MARK2 levels resulted in a different phenotype, which is loss of neuronal polarity. MARK2 kinase activity reduction hindered migration in the developing brain, which was rescued by increasing kinase activity. Our results stress the necessity of maintaining dynamic microtubules for proper neuronal migration. Furthermore, the exact requirements for MARK2 and its kinase activity vary during the course of neuronal migration. Collectively, our results stress the requirements for the different roles of MARK2 during neuronal migration.
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structural variations in the catalytic and ubiquitin associated domains of microtubule associated protein microtubule affinity regulating kinase mark 1 and mark2
Journal of Biological Chemistry, 2006Co-Authors: Alexander Marx, Chanakya Nugoor, Saravanan Panneerselvam, Thomas Timm, Matthias Bilang, Efstratios Mylonas, Eva-maria Mandelkow, Dimitri I. Svergun, Jens MullerAbstract:Abstract The microtubule-associated protein (MAP)/microtubule affinity regulating kinase (MARK)/Par-1 phosphorylates microtubule-associated proteins tau, MAP2, and MAP4 and is involved in the regulation of microtubule-based transport. Par-1, a homologue of MARK in Drosophila and Caenorhabditis elegans, is essential for the development of embryonic polarity. Four isoforms of MARK are found in humans. Recently, we reported the crystal structure of the catalytic and ubiquitin-associated domains of MARK2, an isoform enriched in brain (Panneerselvam, S., Marx, A., Mandelkow, E.-M., and Mandelkow, E. (2006) Structure 14, 173-183). It showed that the ubiquitin-associated domain (UBA) domain has an unusual fold and binds to the N-terminal lobe of the catalytic domain. This is at variance with a previous low resolution structure derived from small angle solution scattering (Jaleel, M., Villa, F., Deak, M., Toth, R., Prescott, A. R., Van Aalten, D. M., and Alessi, D. R. (2006) Biochem. J. 394, 545-555), which predicts binding of the UBA domain to the larger, C-terminal lobe. Here we report the crystal structure of the catalytic and UBA domain of another isoform, MARK1. Although the crystal packing of the two isoforms are unrelated, the overall conformations of the molecules are similar. Notably, the UBA domain has the same unusual conformation as in MARK2, and it binds at the same site. Remarkable differences occur in the catalytic domain at helix C, the catalytic loop, and the activation segment.
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Phosphorylation of MAP2c and MAP4 by MARK kinases leads to the destabilization of microtubules in cells.
Cytoskeleton, 1999Co-Authors: Andreas Ebneth, Gerard Drewes, Eva-maria MandelkowAbstract:Max-Planck Unit for Structural Molecular Biology, Hamburg, Germany Microtubules serve as transport tracks in molecular mechanisms governing cellular shape and polarity. Rapid transitions between stable and dynamic microtubules are regulated by several factors, including microtubule-associated proteins (MAPs). We have shown that MAP/microtubule affinity regulating kinases (MARK) can phosphorylate the microtubule-associated-proteins MAP4, MAP2c, and tau on their microtubule-binding domain in vitro. This leads to their detachment from microtubules (MT) and an increased dynamic instability of MT. Here we show that MARK protein kinases phosphorylate MAP2 and MAP4 on their microtubulebinding domain in transfected CHO cells. In CHO cells expressing MARK1 or MARK2 under control of an inducible promoter, MARK2 phosphorylates an endogenous MAP4-related protein. Prolonged expression of MARK2 results in microtubule-disruption, detachment of cells from the substratum, and cell death. Concomitant with microtubule disruption, we also observed a breakdown of the vimentin network, whereas actin fibers remained unaffected. Thus, MARK seems to play an important role in controlling cytoskeletal dynamics. Cell Motil. Cytoskeleton 44:209‐224, 1999. r 1999 Wiley-Liss, Inc.
Lester Kobzik - One of the best experts on this subject based on the ideXlab platform.
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role of macrophage receptor with collagenous structure in innate immune tolerance
Journal of Immunology, 2013Co-Authors: Jian Jing, Lester Kobzik, Ivana V Yang, Lucy Hui, Jay A Patel, Christopher M Evans, Rytis Prikeris, Brian P Oconnor, David A SchwartzAbstract:Macrophages play a key role in host defense against microbes, in part, through phagocytosis. Macrophage receptor with collagenous structure (MARCO) is a scavenger receptor on the cell surface of macrophages that mediates opsonin-independent phagocytosis. The goal of our study is to investigate the role of MARCO in LPS or lipotechoic acid-induced macrophage tolerance. Although it has been established that expression of MARCO and phagocytosis is increased in tolerant macrophages, the transcriptional regulation and biological role of MARCO in tolerant macrophages have not been investigated. In this study, we confirm that tolerized mouse bone marrow-derived macrophages (BMDM) selectively increase expression of MARCO (both transcript and cell surface receptor) and increase phagocytosis. We found that H3K4me3 dynamic modification of a promoter site of MARCO was increased in tolerized BMDM. Blocking methylation by treatment with 5-aza-2'-deoxycytidine resulted in reduced H3K4me3 binding in the promoter of MARCO, decreased expression of MARCO, and impaired phagocytosis in tolerized BMDM. However, 5-aza-2'-deoxycytidine had no effect on the inflammatory component of innate immune tolerance. In aggregate, we found that histone methylation was critical to MARCO expression and phagocytosis in tolerized macrophages, but did not affect the inflammatory component of innate immune tolerance.
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marco regulates early inflammatory responses against influenza a useful macrophage function with adverse outcome
American Journal of Respiratory Cell and Molecular Biology, 2011Co-Authors: Sanjukta Ghosh, David Gregory, Alexia Smith, Lester KobzikAbstract:Lung macrophages use the scavenger receptor MARCO to bind and ingest bacteria, particulate matter, and post cellular debris. We investigated the role of MARCO in influenza A virus (IAV) pneumonia. In contrast to higher susceptibility to bacterial infection, MARCO−/− mice had lower morbidity and mortality from influenza pneumonia than wild-type (WT) mice. The early course of influenza in MARCO−/− lungs was marked by an enhanced but transient neutrophilic inflammatory response and significantly lower viral replication compared with the WT mice. At later time points, no significant differences in lung histopathology or absolute numbers of T lymphocyte influx were evident. Uptake of IAV by WT and MARCO−/− bronchoalveolar lavage macrophages in vitro was similar. By LPS coadministration, we demonstrated that rapid neutrophil and monocyte influx during the onset of influenza suppressed viral replication, indicating a protective role of early inflammation. We hypothesized that the presence of increased basal proi...
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the scavenger receptor marco is required for lung defense against pneumococcal pneumonia and inhaled particles
Journal of Experimental Medicine, 2004Co-Authors: Mohamed S Arredouani, Karl Tryggvason, Raija Soininen, Zhiping Yang, Yao Yu Ning, Guozhong Qin, Lester KobzikAbstract:Alveolar macrophages (AMs) express the class A scavenger receptor macrophage receptor with collagenous structure (MARCO), but its role in vivo in lung defense against bacteria and environmental particles has not been studied. We used MARCO-deficient mice to directly test the in vivo role of AM MARCO in innate defense against pneumococcal infection and environmental particles. In a murine model of pneumococcal pneumonia, MARCO−/− mice displayed an impaired ability to clear bacteria from the lungs, increased pulmonary inflammation and cytokine release, and diminished survival. In vitro binding of Streptococcus pneumoniae and in vivo uptake of unopsonized particles by MARCO−/− AMs were dramatically impaired. MARCO−/− mice treated with the “inert” environmental particle TiO2 showed enhanced inflammation and chemokine expression, indicating that MARCO-mediated clearance of inert particles by AMs prevents inflammatory responses otherwise initiated by other lung cells. Our findings point to an important role of MARCO in mounting an efficient and appropriately regulated innate immune response against inhaled particles and airborne pathogens.
Davor Plavec - One of the best experts on this subject based on the ideXlab platform.
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predicting future development of copd Marko study
European Respiratory Journal, 2017Co-Authors: Marina Labor, Iva Juric, Zarko Vrbica, Ivan Gudelj, Slavica Labor, Davor PlavecAbstract:Introduction: As COPD is a growing public health problem with increasing morbidity and mortality associated with its progressive nature, early diagnosis and treatment become more and more relevant in management of this disease. Aim and objectives: We aimed to evaluate newly developed health related QoL (HRQoL) questionnaire – Marko questionnaire (Vrbica, Ž. et al. Croat Med J. 2016; 57:425-33.) for the prediction of future development of COPD in a population at risk (active smokers with >20 pack-years). Materials and Methods: These are preliminary data of phase II study of early detection of COPD in at risk cohort recruited by 25 primary care physicians (Marko study); smokers with >20 pack-years, both sexes, aged 40-65 years with no prior diagnosis of COPD. Marko questionnaire is a self-administered one with 18 items and 3 domains. All subjects were referred to a pulmonologist and after a diagnostic workup (history, physical, lung function, HRQoL, exhaled breath temperature (EBT)) diagnosis and severity of COPD was made according to GOLD. EBT was measured before and after a smoked cigarette. Patients were reassessed for a COPD after 2 years. Results: A subsample of 232 subjects (58.6% male), mean (SD) age 52.1 (7.1) yrs with 36.6 (17.3) pack-years of smoking was reassessed after 2 years. We found out that a change in EBT after a cigarette and the second domain of Marko questionnaire were significantly predictive for future COPD (AUC 0.96, p Conclusion: Our preliminary data shows that Marko questionnaire combined with EBT could serve as one of the early markers of future COPD in smokers. ClinicalTrials.gov Identifier: NCT01550679 Supported by unrestricted grant by GlaxoSmithKline (GSK eTrack number CRT114338).
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development and the initial validation of a new self administered questionnaire for an early detection of health status changes in smokers at risk for chronic obstructive pulmonary disease Marko questionnaire
Croatian Medical Journal, 2016Co-Authors: Zarko Vrbica, Marina Labor, Iva Juric, Ivan Gudelj, Slavica Labor, Adrijana Koscec đuknic, Biserka Radosevicvidacek, Peter M A Calverley, Davor PlavecAbstract:Aim To develop and do an initial validation of a new simple tool (self-administered questionnaire) that would be sensitive and specific enough to detect early changes in smokers leading to future development of chronic obstructive pulmonary disease (COPD). Methods 224 consecutive participants (50.9% women), with mean ± standard deviation age of 52.3 ± 6.7 years, 37.5 ± 16.7 pack-years smoking history (85.8% active smokers), and no prior diagnosis of COPD were recruited. The Marko questionnaire was self-administered twice; at the general practitioner’s office and after 2-4 weeks at the tertiary care hospital. Participants were assessed for COPD by a pulmonologist after filling in a quality of life (QoL) questionnaires, historytaking, physical examination, lung function test, 6-minute walk test, and laboratory tests. They were divided into four subgroups: “healthy” smokers, symptomatic smokers, and smokers with mild and moderately severe COPD. Results Psychometric analyses indicated that the 18-item questionnaire had a very good internal consistency (Cronbach’s alpha = 0.91) and test-retest reliability for a four week period (ρc = 0.89, 95% confidence interval [CI] 0.85-0.92, Lin’s concordance). A significant correlations of Marko scores were found with two QoL questionnaires; r = 0.69 (P < 0.001) and r = 0.81 (P < 0.001). Receiver operating characteristic curve analysis showed an area under the curve of 0.753 (95% CI 0.691-0.808, P < 0.001), with a sensitivity of 71.83% and specificity of 64.24% to discriminate “healthy” smokers from other subgroups. Conclusion Based on psychometric analyses and high convergent validity correlation with already validated QoL questionnaires, the newly developed Marko questionnaire was shown to be a reliable self-administered short health status assessment tool.
Mikael C I Karlsson - One of the best experts on this subject based on the ideXlab platform.
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targeting marco and il 37r on immunosuppressive macrophages in lung cancer blocks regulatory t cells and supports cytotoxic lymphocyte function
Cancer Research, 2021Co-Authors: Linnea La Fleur, Johan Botling, Catarina Pelicano, Giorgia Palano, Artur Mezheyeuski, Patrick Micke, Jeffrey V Ravetch, Mikael C I Karlsson, Chikai Zhou, Dhifaf SarhanAbstract:The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment. In non-small cell lung cancer (NSCLC), accumulation of anti-inflammatory tumor-associated macrophages (TAMs) is associated with worse clinical outcome and resistance to therapy. Here we investigated the immune landscape of NSCLC in the presence of pro-tumoral TAMs expressing the macrophage receptor with collagenous structure (MARCO). MARCO-expressing TAM numbers correlated with increased occurrence of regulatory T cells and effector T cells and decreased Natural Killer (NK) cells in these tumors. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL-37. In vitro studies subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an immune-suppressive phenotype through the release of IL-37. MARCO-expressing TAMs blocked cytotoxic T cell and NK cell activation, inhibiting their proliferation, cytokine production, and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL-10 production and diminished CD8 T cell activities. Targeting MARCO or IL-37 receptor (IL-37R) by antibody or CRISPR knockout of IL-37 in lung cancer cell lines repolarized TAMs, resulting in recovered cytolytic activity and anti-tumoral capacity of NK cells and T cells and down-modulated Treg cell activities. In summary, our data demonstrate a novel immune therapeutic approach targeting human TAMs immune suppression of NK and T cell anti-tumor activities.
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targeting marco and il37r on immunosuppressive macrophages in lung cancer blocks regulatory t cells and supports cytotoxic lymphocyte function
Cancer Research, 2021Co-Authors: Linnea La Fleur, Johan Botling, Catarina Pelicano, Giorgia Palano, Artur Mezheyeuski, Patrick Micke, Jeffrey V Ravetch, Mikael C I Karlsson, Chikai Zhou, Dhifaf SarhanAbstract:The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment. In non-small cell lung cancer (NSCLC), accumulation of anti-inflammatory tumor-associated macrophages (TAMs) is associated with worse clinical outcome and resistance to therapy. Here we investigated the immune landscape of NSCLC in the presence of pro-tumoral TAMs expressing the macrophage receptor with collagenous structure (MARCO). MARCO-expressing TAM numbers correlated with increased occurrence of regulatory T cells and effector T cells and decreased Natural Killer (NK) cells in these tumors. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL-37. In vitro studies subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an immune-suppressive phenotype through the release of IL-37. MARCO-expressing TAMs blocked cytotoxic T cell and NK cell activation, inhibiting their proliferation, cytokine production, and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL-10 production and diminished CD8 T cell activities. Targeting MARCO or IL-37 receptor (IL-37R) by antibody or CRISPR knockout of IL-37 in lung cancer cell lines repolarized TAMs, resulting in recovered cytolytic activity and anti-tumoral capacity of NK cells and T cells and down-modulated Treg cell activities. In summary, our data demonstrate a novel immune therapeutic approach targeting human TAMs immune suppression of NK and T cell anti-tumor activities.
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720 targeting marco and il 37r on anti inflammatory macrophages in lung cancer blocks regulatory t cells and shift balance to support cytotoxic lymphocyte function
Journal for ImmunoTherapy of Cancer, 2020Co-Authors: Linnea La Fleur, Johan Botling, Catarina Pelicano, Giorgia Palano, Artur Mezheyeuski, Patrick Micke, Jeffrey V Ravetch, Mikael C I Karlsson, Dhifaf SarhanAbstract:Background The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment (TME). In non-small cell lung cancer (NSCLC) accumulation of anti-inflammatory tumor-associated macrophages (TAMs) is associated with worse clinical outcome and resistance to therapy. Numerous clinical trials aiming to recover T cell anti-tumor activity have been failing due to the persistence immune suppression in TME. Thus, there is a clinical need for alternative treatments targeting the suppressive function of the TME. We have previously shown that antibodies targeting the scavenger receptor MARCO reprograms the pro-tumoral TAMs in murine cancer models. Here, we investigated the immune landscape of NSCLC in the presence of MARCO expressing TAMs. We tested targeting MARCO or the tumor mechanisms inducing MARCO on human TAMs and hypothesized that targeting these mechanisms will remodel the suppressive environment and relive the anti-tumor responses to increase the efficacy of immunotherapy. Methods To test our hypothesis, we first investigated the immune landscape of NSCLC in the presence of pro-tumoral MARCO+TAMs compared with tumors infiltrated by MARCO-TAMs. We next used RNAseq to analyze differential gene expression in NSCLC tumors infiltrated by MARCO positive or negative macrophages. In vitro, cytokine differentiated macrophages alternatively cultured with lung cancer cell lines were co-cultured with Natural Killer (NK) cells and T cells to mimic their interaction in the TME. Later, macrophages were treated with targeting antibodies and their phenotype and function were examined prior and following interaction with other immune cells. Results We found that MARCO expressing TAM numbers correlated with increased occurrence of regulatory T cell and effector T cells and decreased NK cells in NSCLC infiltrated by MARCO+TAMs. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL-37. Studies in vitro subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an anti-inflammatory phenotype through the release of IL-37. These human MARCO expressing TAMs blocked cytotoxic T cell and NK cell activation, inhibiting their proliferation, cytokine production and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL-10 production and diminished CD8 T cell activities. Targeting MARCO or IL-37 receptor (IL-37R) repolarized TAMs resulted in recovered cytolytic activity and anti-tumoral capacity of NK cells and T cells. Conclusions In summary, our data demonstrate a novel immune therapeutic approach targeting human TAM immune suppression of NK and T cell anti-tumor activities and remodel immune suppression. Ethics Approval The study was approved by Institutional Ethics Board, approval number Dnr 2013.977-31.1.
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cutting edge marginal zone macrophages regulate antigen transport by b cells to the follicle in the spleen via cd21
Journal of Immunology, 2016Co-Authors: Kajsa E Prokopec, Annamaria Georgoudaki, Silke Sohn, Fredrik Wermeling, Hans Gronlund, Emma Lindh, Michael C Carroll, Mikael C I KarlssonAbstract:Marginal zone macrophages (MZM) are strategically located in the spleen, lining the marginal sinus where they sense inflammation and capture Ag from the circulation. One of the receptors expressed by MZM is scavenger receptor macrophage receptor with collagenous structure (MARCO), which has affinity for modified self-antigens. In this article, we show that engagement of MARCO on murine macrophages induces extracellular ATP and loss of CD21 and CD62L on marginal zone B cells. Engagement of MARCO also leads to reduction of Ag transport by marginal zone B cells and affects the subsequent immune response. This study highlights a novel function for MZM in regulating Ag transport and activation, and we suggest that MARCO-dependent ATP release regulates this through shedding of CD21 and CD62L. Because systemic lupus erythematosus patients were shown to acquire autoantibodies against MARCO, this highlights a mechanism that could affect a patient's ability to combat infections.
Karl Tryggvason - One of the best experts on this subject based on the ideXlab platform.
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sr a marco mediated ligand delivery enhances intracellular tlr and nlr function but ligand scavenging from cell surface limits tlr4 response to pathogens
Blood, 2011Co-Authors: Subhankar Mukhopadhyay, Audrey Varin, Yunying Chen, Baoying Liu, Karl Tryggvason, Siamon GordonAbstract:Phagocytic and pathogen sensing receptors are responsible for particle uptake and inflammation. It is unclear how these receptors' systems influence each other's function to shape an innate response. The class-A scavenger receptors SR-A (scavenger receptor A) and MARCO (macrophage receptor with collagenous structure) are 2 well-characterized phagocytic receptors that are unable to initiate inflammatory responses by themselves, yet are implicated in the pathogenesis of various inflammatory disorders. However, the mechanism for such an apparent discrepancy is still unclear. We utilized SR-A(-/-), MARCO(-/-), and SR-A(-/-)-MARCO(-/-) mice, along with microbe-derived, environmental, and synthetic polyanions to assess the inflammatory responses following combinatorial ligation of SR-A/MARCO and selected Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) by their shared ligands. In addition to ligating SR-A and MARCO, these agonists also selectively activated the cell-surface sensor TLR4, endosomal TLR3, and the cytosolic NOD2 and NALP3 (NACHT domain-, leucine-rich repeat-, and pyrin domain-containing protein 3). We show that, following recognition of common ligands, SR-A and MARCO attenuate TLR4-mediated responses while enhancing responses by the intracellular TLR3, NOD2, and NALP3. We conclude that SR-A/MARCO-mediated rapid ligand internalization prevented sensing by surface TLRs while increasing ligand availability in intracellular compartments, thus allowing sensing and robust responses by intracellular sensors.
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marco tlr2 and cd14 are required for macrophage cytokine responses to mycobacterial trehalose dimycolate and mycobacterium tuberculosis
PLOS Pathogens, 2009Co-Authors: Dawn M E Bowdish, Subhankar Mukhopadhyay, Karl Tryggvason, Siamon Gordon, Kaori Sakamoto, Mariliis Kroos, Cynthia A Leifer, David G RussellAbstract:Virtually all of the elements of Mycobacterium tuberculosis (Mtb) pathogenesis, including pro-inflammatory cytokine production, granuloma formation, cachexia, and mortality, can be induced by its predominant cell wall glycolipid, trehalose 6,6′-dimycolate (TDM/cord factor). TDM mediates these potent inflammatory responses via interactions with macrophages both in vitro and in vivo in a myeloid differentiation factor 88 (MyD88)-dependent manner via phosphorylation of the mitogen activated protein kinases (MAPKs), implying involvement of toll-like receptors (TLRs). However, specific TLRs or binding receptors for TDM have yet to be identified. Herein, we demonstrate that the macrophage receptor with collagenous structure (MARCO), a class A scavenger receptor, is utilized preferentially to “tether” TDM to the macrophage and to activate the TLR2 signaling pathway. TDM-induced signaling, as measured by a nuclear factor-kappa B (NF-κB)-luciferase reporter assay, required MARCO in addition to TLR2 and CD14. MARCO was used preferentially over the highly homologous scavenger receptor class A (SRA), which required TLR2 and TLR4, as well as their respective accessory molecules, in order for a slight increase in NF-κB signaling to occur. Consistent with these observations, macrophages from MARCO−/− or MARCO−/−SRA−/− mice are defective in activation of extracellular signal-related kinase 1/2 (ERK1/2) and subsequent pro-inflammatory cytokine production in response to TDM. These results show that MARCO-expressing macrophages secrete pro-inflammatory cytokines in response to TDM by cooperation between MARCO and TLR2/CD14, whereas other macrophage subtypes (e.g. bone marrow–derived) may rely somewhat less effectively on SRA, TLR2/CD14, and TLR4/MD2. Macrophages from MARCO−/− mice also produce markedly lower levels of pro-inflammatory cytokines in response to infection with virulent Mtb. These observations identify the scavenger receptors as essential binding receptors for TDM, explain the differential response to TDM of various macrophage populations, which differ in their expression of the scavenger receptors, and identify MARCO as a novel component required for TLR signaling.
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marco an innate activation marker of macrophages is a class a scavenger receptor for neisseria meningitidis
European Journal of Immunology, 2006Co-Authors: Subhankar Mukhopadhyay, Yunying Chen, Karl Tryggvason, Marko Sankala, Leanne Peiser, Timo Pikkarainen, Georg Kraal, Siamon GordonAbstract:The scavenger receptor-A I/II (SR-A) and macrophage receptor with collagenous domain (MARCO) share a common domain organisation and ligand repertoire, including selected polyanions and gram-positive and -negative organisms, but differ in fine specificity of ligand binding, tissue distribution and regulation. Neisseria meningitidis (NM) is a selective ligand for SR-A, but there is evidence for an additional SR-A-independent, polyanion-sensitive component for NM recognition. We therefore studied the relative contribution of MARCO and SR-A to binding of NM by resident and elicited peritoneal macrophages obtained from MARCO-/-, SR-A-/- and SR-A-MARCO-/- mice. Results confirmed that both mouse and human MARCO are able to bind NM independently of NM LPS. MARCO and SR-A contributed independently to NM binding, correlating with their expression levels in different cell populations, but neither of these two molecules was required for release of TNF-alpha and nitric oxide. We propose that the TLR-dependent induction of MARCO by innate immune stimulation enhances recognition and uptake of pathogenic organisms such as NM, thus contributing to host defence against infection.
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defective microarchitecture of the spleen marginal zone and impaired response to a thymus independent type 2 antigen in mice lacking scavenger receptors marco and sr a
Journal of Immunology, 2005Co-Authors: Yunying Chen, Tatsuhiko Kodama, Timo Pikkarainen, Georg Kraal, Outi Elomaa, Raija Soininen, Karl TryggvasonAbstract:The macrophage scavenger receptor macrophage receptor with a collagenous structure (MARCO) is expressed in mice by the marginal zone macrophages of the spleen and by macrophages of the medullary cords of lymph nodes, as well as the peritoneal macrophages. MARCO is a relative of scavenger receptor A (SR-A), the more widely expressed prototypic member of the scavenger receptor family. In the present study, we found that genetic ablation of MARCO leads to changes in the organization of the splenic marginal zone, and causes a significant reduction in the size of the resident peritoneal macrophage population, possibly due to changes in adhesion and migration capacity. In mice lacking both MARCO and SR-A these effects are even more apparent. During ontogeny, the appearance and organization of the MARCO-expressing cells in the spleen precedes the appearance of other receptors on macrophages in the marginal zone, such as SIGNR1 and Siglec-1. In the absence of MARCO, a clear delay in the organization of the marginal zone was observed. Similar findings were seen when the reappearance of the various subsets from precursors was studied after depleting macrophages from the adult spleen by a liposome treatment. When challenged with a pneumococcal polysaccharide vaccine, a T-independent type 2 Ag for which an intact marginal zone is crucial, the knockout mice exhibited a clearly impaired response. These findings suggest that both MARCO and SR-A, in addition to being important scavenger receptors, could be involved in the positioning and differentiation of macrophages, possibly through interaction with endogenous ligands.
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the scavenger receptor marco is required for lung defense against pneumococcal pneumonia and inhaled particles
Journal of Experimental Medicine, 2004Co-Authors: Mohamed S Arredouani, Karl Tryggvason, Raija Soininen, Zhiping Yang, Yao Yu Ning, Guozhong Qin, Lester KobzikAbstract:Alveolar macrophages (AMs) express the class A scavenger receptor macrophage receptor with collagenous structure (MARCO), but its role in vivo in lung defense against bacteria and environmental particles has not been studied. We used MARCO-deficient mice to directly test the in vivo role of AM MARCO in innate defense against pneumococcal infection and environmental particles. In a murine model of pneumococcal pneumonia, MARCO−/− mice displayed an impaired ability to clear bacteria from the lungs, increased pulmonary inflammation and cytokine release, and diminished survival. In vitro binding of Streptococcus pneumoniae and in vivo uptake of unopsonized particles by MARCO−/− AMs were dramatically impaired. MARCO−/− mice treated with the “inert” environmental particle TiO2 showed enhanced inflammation and chemokine expression, indicating that MARCO-mediated clearance of inert particles by AMs prevents inflammatory responses otherwise initiated by other lung cells. Our findings point to an important role of MARCO in mounting an efficient and appropriately regulated innate immune response against inhaled particles and airborne pathogens.