David M Mosser

Loyola University Maryland, Baltimore, Maryland, United States

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Publications (128)688.24 Total impact

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    ABSTRACT: Parasites of the genus Leishmania are the causative agents of leishmaniasis, a group of diseases that range in manifestations from skin lesions to fatal visceral disease. The life cycle of Leishmania parasites is split between its insect vector and its mammalian host, where it resides primarily inside of macrophages. Once intracellular, Leishmania parasites must evade or deactivate the host's innate and adaptive immune responses in order to survive and replicate. We performed transcriptome profiling using RNA-seq to simultaneously identify global changes in murine macrophage and L. major gene expression as the parasite entered and persisted within murine macrophages during the first 72 h of an infection. Differential gene expression, pathway, and gene ontology analyses enabled us to identify modulations in host and parasite responses during an infection. The most substantial and dynamic gene expression responses by both macrophage and parasite were observed during early infection. Murine genes related to both pro- and anti-inflammatory immune responses and glycolysis were substantially upregulated and genes related to lipid metabolism, biogenesis, and Fc gamma receptor-mediated phagocytosis were downregulated. Upregulated parasite genes included those aimed at mitigating the effects of an oxidative response by the host immune system while downregulated genes were related to translation, cell signaling, fatty acid biosynthesis, and flagellum structure. The gene expression patterns identified in this work yield signatures that characterize multiple developmental stages of L. major parasites and the coordinated response of Leishmania-infected macrophages in the real-time setting of a dual biological system. This comprehensive dataset offers a clearer and more sensitive picture of the interplay between host and parasite during intracellular infection, providing additional insights into how pathogens are able to evade host defenses and modulate the biological functions of the cell in order to survive in the mammalian environment.
    Preview · Article · Dec 2015 · BMC Genomics
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    ABSTRACT: Loss-of-function mutations in the dysferlin gene (DYSF) result in a family of muscle disorders known collectively as the dysferlinopathies. Dysferlin-deficient muscle is characterized by inflammatory foci and macrophage infiltration with subsequent decline in muscle function. Whereas macrophages function to remove necrotic tissue in acute injury, their prevalence in chronic myopathy is thought to inhibit resolution of muscle regeneration. Two major classes of macrophages, classical (M1) and alternative (M2a), play distinct roles during the acute injury process. However, their individual roles in chronic myopathy remain unclear and were explored in this study. To test the roles of the two macrophage phenotypes on regeneration in dysferlin-deficient muscle, we developed an in vitro co-culture model of macrophages and muscle cells. We assayed the co-cultures using ELISA and cytokine arrays to identify secreted factors and performed transcriptome analysis of molecular networks induced in the myoblasts. Dysferlin-deficient muscle contained an excess of M1 macrophage markers, compared with WT, and regenerated poorly in response to toxin injury. Co-culturing macrophages with muscle cells showed that M1 macrophages inhibit muscle regeneration whereas M2a macrophages promote it, especially in dysferlin-deficient muscle cells. Examination of soluble factors released in the co-cultures and transcriptome analysis implicated two soluble factors in mediating the effects: IL-1β and IL-4, which during acute injury are secreted from M1 and M2a macrophages, respectively. To test the roles of these two factors in dysferlin-deficient muscle, myoblasts were treated with IL-4, which improved muscle differentiation, or IL-1β, which inhibited it. Importantly, blockade of IL-1β signaling significantly improved differentiation of dysferlin-deficient cells. We propose that the inhibitory effects of M1 macrophages on myogenesis are mediated by IL-1β signals and suppression of the M1-mediated immune response may improve muscle regeneration in dysferlin deficiency. Our studies identify a potential therapeutic approach to promote muscle regeneration in dystrophic muscle.
    Full-text · Article · Dec 2015 · Skeletal Muscle
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    ABSTRACT: The priming of macrophages with IFN-γ prior to TLR stimulation results in enhanced and prolonged inflammatory cytokine production. In this study, we demonstrate that, following TLR stimulation, macrophages upregulate the adenosine 2b receptor (A2bR) to enhance their sensitivity to immunosuppressive extracellular adenosine. This upregulation of A2bR leads to the induction of macrophages with an immunoregulatory phenotype and the downregulation of inflammation. IFN-γ priming of macrophages selectively prevents the induction of the A2bR in macrophages to mitigate sensitivity to adenosine and to prevent this regulatory transition. IFN-γ-mediated A2bR blockade leads to a prolonged production of TNF-α and IL-12 in response to TLR ligation. The pharmacologic inhibition or the genetic deletion of the A2bR results in a hyperinflammatory response to TLR ligation, similar to IFN-γ treatment of macrophages. Conversely, the overexpression of A2bR on macrophages blunts the IFN-γ effects and promotes the development of immunoregulatory macrophages. Thus, we propose a novel mechanism whereby IFN-γ contributes to host defense by desensitizing macrophages to the immunoregulatory effects of adenosine. This mechanism overcomes the transient nature of TLR activation, and prolongs the antimicrobial state of the classically activated macrophage. This study may offer promising new targets to improve the clinical outcome of inflammatory diseases in which macrophage activation is dysregulated.
    No preview · Article · Sep 2015 · The Journal of Immunology
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    ABSTRACT: Protozoan parasites of the genus Leishmania are the etiological agents of leishmaniasis, a group of diseases with a worldwide incidence of 0.9-1.6 million cases per year. We used RNA-seq to conduct a high-resolution transcriptomic analysis of the global changes in gene expression and RNA processing events that occur as L. major transforms from non-infective procyclic promastigotes to infective metacyclic promastigotes. Careful statistical analysis across multiple biological replicates and the removal of batch effects provided a high quality framework for comprehensively analyzing differential gene expression and transcriptome remodeling in this pathogen as it acquires its infectivity. We also identified precise 5' and 3' UTR boundaries for a majority of Leishmania genes and detected widespread alternative trans-splicing and polyadenylation. An investigation of possible correlations between stage-specific preferential trans-splicing or polyadenylation sites and differentially expressed genes revealed a lack of systematic association, establishing that differences in expression levels cannot be attributed to stage-regulated alternative RNA processing. Our findings build on and improve existing expression datasets and provide a substantially more detailed view of L. major biology that will inform the field and potentially provide a stronger basis for drug discovery and vaccine development efforts. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
    Preview · Article · Jul 2015 · Nucleic Acids Research
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    ABSTRACT: Macrophages readily change their phenotype in response to exogenous stimuli. In this work, macrophages were stimulated under a variety of experimental conditions, and phenotypic alterations were correlated with changes in gene expression. We identified 3 transcriptionally related populations of macrophages with immunoregulatory activity. They were generated by stimulating cells with TLR ligands in the presence of 3 different "reprogramming" signals: high-density ICs, PGE2, or Ado. All 3 of these cell populations produced high levels of transcripts for IL-10 and growth and angiogenic factors. They also secreted reduced levels of inflammatory cytokines IL-1β, IL-6, and IL-12. All 3 macrophage phenotypes could partially rescue mice from lethal endotoxemia, and therefore, we consider each to have anti-inflammatory activity. This ability to regulate innate-immune responses occurred equally well in macrophages from STAT6-deficient mice. The lack of STAT6 did not affect the ability of macrophages to change cytokine production reciprocally or to rescue mice from lethal endotoxemia. Furthermore, treatment of macrophages with IL-4 failed to induce similar phenotypic or transcriptional alterations. This work demonstrates that there are multiple ways to generate macrophages with immunoregulatory activity. These anti-inflammatory macrophages are transcriptionally and functionally related to each other and are quite distinct from macrophages treated with IL-4. © Society for Leukocyte Biology.
    Full-text · Article · Jun 2015 · Journal of leukocyte biology
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    ABSTRACT: We evaluated the role of IL-18 during Leishmania amazonensis infection in C57BL/6 mice, using IL-18KO mice. We showed that IL-18 is involved in susceptibility to L. amazonensis, since IL-18KO mice presented reduced lesions and parasite loads. Because macrophages are the host cells of the parasite, we investigated if macrophages were involved in IL-18-mediated susceptibility to L. amazonensis. We showed that macrophages obtained from WT or IL-18KO responded similarly to L. amazonensis infection. Moreover, we showed that C57BL/6 macrophages do not respond to IL-18, since they do not express IL-18R. Therefore, macrophages are not involved in IL-18-mediated susceptibility to L. amazonensis. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · May 2015 · Cytokine
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    ABSTRACT: Introduction Cutaneous leishmaniasis (CL) due to L.braziliensis infection is characterized by a strong inflammatory response with high levels of TNF and ulcer development. Less attention has been given to the role of mononuclear phagocytes to this process. Monocytes constitute a heterogeneous population subdivided into classical, intermediate and non-classical, and are known to migrate to inflammatory sites and secrete inflammatory mediators. TNF participates in the induction of matrix metalloproteinases (MMPs). MMP-9 is an enzyme that degrades basal membrane and its activity is controlled by the tissue inhibitor of metalloproteinase. Methods Mononuclear cells were obtained from ex-vivo labeling sub-populations of monocytes and MMP-9, and the frequency was determined by flow cytometry. Culture was performed during 72 hours, stimulating the cells with SLA, levels of MMP-9 and TIMP-1 in the supernatants were determined by ELISA. Results We observed that cells from CL lesions secrete high amounts of MMP-9 when compared to healthy subjects. Although MMP-9 was produced by monocytes, non-classical ones were the main source of this enzyme. We also observed that TNF produced in high level during CL contributes to MMP-9 production. Conclusions These observations emphasize the role of monocytes, TNF and MMP-9 in the pathogenesis of L. braziliensis infection.
    Full-text · Article · Nov 2014 · PLoS Neglected Tropical Diseases

  • No preview · Article · Aug 2014
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    ABSTRACT: Ulcer development in patients with cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is associated with high levels of tumor necrosis factor (TNF). We found that early after infection, before ulcer development, the frequency of CD16+ (both intermediate [CD14+CD16+] and nonclassical [CD14dimCD16+]) monocytes was increased in the peripheral blood of patients with L. braziliensis, compared with uninfected controls. These results suggest that CD16+ monocytes might promote disease. Also, we found that intermediate monocytes expressed CCR2 and that increased levels of CCL2 protein were present in lesions from patients, suggesting that intermediate monocytes are more likely than nonclassical monocytes to migrate to the lesion site. Finally, we found that the intermediate monocytes produced TNF. Our results show that intermediate monocytes are increased in frequency soon after infection; express CCR2, which would promote their migration into the lesions; and, owing to their production of TNF, can enhance the inflammatory response.
    Full-text · Article · Aug 2014 · The Journal of Infectious Diseases
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    ABSTRACT: Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated macrophages, often termed M1 and M2. Here, we describe a set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation-with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for macrophage-activation nomenclature.
    Full-text · Article · Jul 2014 · Immunity
  • David M. Mosser · C. Andrew Stewart
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    ABSTRACT: Macrophages are a physiologically diverse collection of cells whose function can vary tremendously depending upon their anatomical location and the stimuli to which they are exposed. The plasticity of macrophages allows them to assume diametrically opposed physiologies and their ability to rapidly change their physiology in response to environmental cues permits these cells to be major mediators of homeostasis. On one hand macrophages can produce toxic mediators that can kill pathogens and promote immune responses. On the other, they can inhibit immune responses and orchestrate wound healing and tissue repair. The fact that macrophages with opposite physiologies can exist in an organism argues that a strategy to deplete macrophages would likely be ineffective, because it would deplete cells on both ends of the spectrum. In order to focus attention on the diverse roles of these cells, several investigators have attempted to assign names associated with given functional states, despite the fact that most acknowledge that these states can rapidly change. In fact, we once suggested that assigning a functional name to a rapidly changing population of macrophages was analogous to assigning a color to a chameleon, only to discover that no fewer than two other groups had previously made similar analogies. The assigning of names to macrophage populations based on their major activity, limitations notwithstanding, allows investigators to identify these cells in tissue or to direct drugs to specific subpopulations of macrophages in order to modulate immune responses. In this chapter we consider regulatory macrophages to be a broad general category of macrophages that are grouped by their functional activity. These activities include mitigating inflammation, regulating immune responses, and perhaps participating in tissue regeneration. We do not imply that all regulatory macrophages are identical. Rather, we propose that phenotypically diverse regulatory macrophages arise in response to a variety of exogenous and endogenous stimuli. We propose that all these regulatory macrophages share a common regulatory gene expression program leading to a reduced production of inflammatory mediators, and increased production of immunoregulatory cytokines and growth factors. We propose that these cells are major mediators of homeostasis and that without regulatory macrophages normal immune/inflammatory responses would invariably progress to immunopathology. Finally, we suggest that a part of the standard response of macrophages to inflammatory stimuli is the gradual transition from an inflammatory to a regulatory macrophage. This implies that macrophages can regulate their own physiology. © 2014 Springer Science+Business Media New York. All rights reserved.
    No preview · Article · May 2014
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    Heather B Cohen · David M Mosser
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    ABSTRACT: A study by Epelman et al. (2014) in this issue of Immunity demonstrates that diverse subpopulations of macrophages reside in the adult heart and can be maintained by multiple mechanisms involving both local proliferation and contributions from monocytes.
    Preview · Article · Jan 2014 · Immunity
  • Rahul Suresh · David M Mosser
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    ABSTRACT: Infection by pathogenic microbes initiates a set of complex interactions between the pathogen and the host mediated by pattern recognition receptors. Innate immune responses play direct roles in host defense during the early stages of infection, and they also exert a profound influence on the generation of the adaptive immune responses that ensue. An improved understanding of the pattern recognition receptors that mediate innate responses and their downstream effects after receptor ligation has the potential to lead to new ways to improve vaccines and prevent autoimmunity. This review focuses on the control of innate immune activation and the role that innate immune receptors play in helping to maintain tissue homeostasis.
    No preview · Article · Dec 2013 · AJP Advances in Physiology Education
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    Full-text · Article · Nov 2013 · Infection and immunity
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    ABSTRACT: Neutrophils are involved in early stages of immune responses to pathogens. Here, we investigated the role of neutrophils during the establishment of Leishmania amazonensis infection in BALB/c and C57BL/6 mice. First, we showed an accumulation of neutrophils between 6 and 24 hours post-infection, followed by a reduction in neutrophil numbers after 72 hours. Next, we depleted neutrophils prior to infection using RB6-8C5 or 1A8 mAb. Neutrophil depletion led to faster lesion development, increased parasite numbers and higher arginase activity during the first week of infection in BALB/c mice, but not in C57BL/6 mice. Increased susceptibility was accompanied by augmented levels of anti-L. amazonensis IgG and increased production of IL-10 and IL-17. Because IL-10 is a mediator of susceptibility to Leishmania infection, we blocked IL-10 signaling in neutrophil-depleted mice using anti-IL-10R. Interestingly, inhibition of IL-10 signaling abrogated the increase in parasite loads observed in neutrophil-depleted mice, suggesting that parasite proliferation is at least partially mediated by IL-10. Additionally, we tested the effect of IL-17 in inflammatory macrophages and observed that IL-17 increased arginase activity and favored parasite growth. Taken together, our data indicate that neutrophils control parasite numbers and limit lesion development during the first week of infection in BALB/c mice. This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2013 · Parasite Immunology

  • No preview · Conference Paper · Sep 2013
  • Heather B Cohen · David M Mosser
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    ABSTRACT: Macrophages make major contributions to inflammatory immunopathology. In this work, we examine three disease scenarios, in which M1s play a major role early in the disease but eventually transitions into a population of cells with immunoregulatory activity. We propose that the transition from an inflammatory to a regulatory phenotype is a natural progression that regularly occurs in stimulated macrophages and that the timing of this transition is critical to maintaining homeostasis. In the first section of this review, we discuss the exogenous microenvironmental cues that may induce macrophages to enter a regulatory state. In the second half of this review, we discuss a novel mechanism, whereby TLR-stimulated macrophages can intrinsically induce their own regulatory activation state. They do so by secreting and synthesizing endogenous "reprogramming" signals that work in an autocrine fashion to promote a regulatory phenotype. We propose that these endogenous regulatory mechanisms exist to prevent macrophage-mediated immunopathology. Thus, macrophages can respond to endogenous and exogenous cues to regulate their activation state, and without these controlled regulatory responses, M1 would persist to the detriment of the host.
    No preview · Article · Aug 2013 · Journal of leukocyte biology
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    ABSTRACT: Sepsis is a highly fatal disease caused by an initial hyper-inflammatory response followed by a state of profound immunosuppression. While, it is well-appreciated that the initial production of pro-inflammatory cytokines by macrophages accompanies the onset of sepsis, it remains unclear what causes the transition to an immunosuppressive state. In this study, we reveal that macrophages themselves are key regulators of this transition, and that the surface enzyme CD39 plays a critical role in self-limiting the activation process. We demonstrate that TLR-stimulated macrophages modulate their activation state by increasing the synthesis and secretion of ATP. This endogenous ATP is paradoxically immunosuppressive due to its rapid catabolism into adenosine by CD39. Macrophages lacking CD39 are unable to transition to a regulatory state and consequently continue to produce inflammatory cytokines. The importance of this transition is demonstrated in a mouse model of sepsis, where small numbers of CD39-deficient macrophages were sufficient to induce lethal endotoxic shock. Thus, these data implicate CD39 as a key 'molecular switch' that allows macrophages to self-limit their activation state. We propose that therapeutics targeting the release and hydrolysis of ATP by macrophages may represent new ways to treat inflammatory diseases.
    Full-text · Article · Aug 2013 · Blood
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    ABSTRACT: Cutaneous leishmaniasis (CL) caused by L. braziliensis is characterized by the presence of one or more ulcerated lesions with elevated borders. Cellular infiltrate in lesions of these individuals are composed mainly by mononuclear cells, including CD4+, CD8+, plasm cells and cells from myeloid lineage. High levels of IFN-γ and TNF-α are detected in these patients and these proinflammatory cytokines are known to play a role in the pathogenesis of CL, by inducing tissue damage. Upon infection with Leishmania or in presence of soluble Leishmania antigen, monocytes from CL individuals produce high levels of TNF-alpha and chemokines involved in recruitment of CD4+, CD8+ T cells and monocytes. Recent studies have shown that circulating monocytes constitute a heterogeneous population, and based on expression of CD14 and CD16, these cells can be divided in classical (CD14+CD16−), intermediate (CD14+CD16+) and non-classical (CD14−CD16+) monocytes. Intermediate and non-classical monocytes are known to migrate to inflamed sites and secrete inflammatory mediators, and high frequency of these cells has been associated with pathogenesis of many inflammatory diseases. TNF-α can mediate the pathology of the disease through various mechanisms including induction of nitric oxide, apoptosis, expression of metalloproteinases (MMPs) and increased cytotoxicity. MMP-9 is a zinc-dependent enzyme that degrades collagen type 4 (present in basal membrane) and has been associated with skin inflammatory diseases. Although the mechanism underlying ulcer development in CL is not known, it is likely that MMP-9 contribute to tissue damage since it was documented that L. braziliensis-infected macrophages upregulate MMP-9.Methods Peripheral blood mononuclear cells were obtained from patients with cutaneous leishmaniasis and uninfected controls. Cells were analysed ex-vivo or after culture in presence of Leishmania parasites, antigen or LPS, for MHC II, co-stimulatory molecules, TNF-alpha and MMP9.ResultsThus, our goal was to investigate the contribution of sub-populations of monocytes to TNF-alpha and MMP-9 secretion in CL patients. We found that early after infection (pre-ulcerative phase) the frequency of intermediate and non-classical monocytes are elevated in blood of CL individuals. Also, while intermediate monocytes produced more TNF-alpha in response to Leishmania, non-classical ones were the main source of MMP-9 in most CL patients. Similarly, the biopsies studies reveled that the non-classical monocytes were the main MMP-9 producing cells.Conclusion These results show that monocytes subpopulations contribute differently to the immunopathology observed in CL patients.
    No preview · Article · Sep 2012 · Cytokine
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    Volker Briken · David M Mosser

    Preview · Article · Nov 2011 · Journal of leukocyte biology

Publication Stats

11k Citations
688.24 Total Impact Points


  • 2009-2015
    • Loyola University Maryland
      Baltimore, Maryland, United States
  • 2001-2015
    • University of Maryland, College Park
      • Department of Cell Biology & Molecular Genetics
      CGS, Maryland, United States
  • 2010
    • Federal University of Minas Gerais
      • Departamento de Anatomia Patológica e Medicina Legal
      Cidade de Minas, Minas Gerais, Brazil
  • 2007-2010
    • Max Planck Institute of Molecular Cell Biology and Genetics
      Dresden, Saxony, Germany
  • 1990-2001
    • Temple University
      • • Department of Microbiology and Immunology
      • • Fels Institute for Cancer Research and Molecular Biology
      Filadelfia, Pennsylvania, United States
  • 1999
    • Bradford School
      Pittsburgh, Pennsylvania, United States
  • 1997
    • The Rockefeller University
      New York, New York, United States
  • 1987
    • New York Downtown Hospital
      New York, New York, United States
    • Cornell University
      Итак, New York, United States