David M Mosser

University of Maryland, College Park, Maryland, United States

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Publications (114)562.45 Total impact

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    ABSTRACT: 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.
    PLoS Neglected Tropical Diseases 11/2014; 8(11):e3282. DOI:10.1371/journal.pntd.0003282 · 4.49 Impact Factor
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    ABSTRACT: Ulcer development in cutaneous leishmaniasis (CL) patients caused by Leishmania braziliensis is associated with high levels of TNF. We found that early after infection, before ulcer development, the frequency of CD16+ (both intermediate (CD14+CD16+) and non-classical (CD14(dim)CD16+)) monocytes was increased in the peripheral blood of L. braziliensis patients compared to 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 to migrate to the lesion site than non-classical monocytes. 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 due to TNF production can enhance the inflammatory response.
    The Journal of Infectious Diseases 08/2014; DOI:10.1093/infdis/jiu439 · 5.78 Impact Factor
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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.
    Immunity 07/2014; 41(1):14-20. DOI:10.1016/j.immuni.2014.06.008 · 19.75 Impact Factor
  • 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.
    Immunity 01/2014; 40(1):3-5. DOI:10.1016/j.immuni.2013.12.005 · 19.75 Impact Factor
  • 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.
    AJP Advances in Physiology Education 12/2013; 37(4):284-91. DOI:10.1152/advan.00058.2013 · 1.24 Impact Factor
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    JOANNE M. MANNS, DAVID M. MOSSER, HELEN R. BUCKLEY
    Infection and immunity 11/2013; · 4.16 Impact Factor
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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.
    Parasite Immunology 09/2013; 36(1). DOI:10.1111/pim.12078 · 1.85 Impact Factor
  • 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.
    Journal of leukocyte biology 08/2013; 94(5). DOI:10.1189/jlb.0413236 · 4.99 Impact Factor
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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.
    Blood 08/2013; 122(11). DOI:10.1182/blood-2013-04-496216 · 9.78 Impact Factor
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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.
    Cytokine 09/2012; 59(3):527-528. DOI:10.1016/j.cyto.2012.06.113 · 2.87 Impact Factor
  • Volker Briken, David M Mosser
    Journal of leukocyte biology 11/2011; 90(5):839-41. DOI:10.1189/jlb.0411203 · 4.99 Impact Factor
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    David M Mosser, Xia Zhang
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    ABSTRACT: Phagocytosis is a cellular process that plays crucial roles in the removal of dead or dying cells, tissue remodeling, and host defense against invading pathogens. Most eukaryotic cells are decorated with glycoproteins containing terminal sialic acids, whose negative charges tend to repel cells, making so-called "nonspecific" phagocytosis a relatively inefficient process. Professional phagocytes are so designated because they express two major classes of receptors on their surfaces that are primarily involved in phagocytosis. Paradoxically, these receptors do not recognize microbes directly, but rather endogenous proteins that become tethered to microbes and target them for destruction. These are the Fcγ receptors that bind to the Fc portion of IgG and the complement receptors (CRs), which bind primarily to cleavage products of the third component of complement, C3. This unit describes assays that are used to measure these two types of macrophage phagocytosis.
    Current protocols in immunology / edited by John E. Coligan ... [et al.] 11/2011; Chapter 14:Unit 14.27. DOI:10.1002/0471142735.im1427s95
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    Bryan D Fleming, David M Mosser
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    ABSTRACT: Macrophages exhibit remarkable plasticity and can change their phenotype in response to different environmental cues. They can become activated to kill intracellular microbes or they can assume regulatory properties to modulate immune responses. Regulatory macrophages are fundamentally different from classically activated, and we propose from non-classically activated macrophages; they arise in response to different stimuli and perform different physiological functions. They are likely to express unique biochemical markers that could be exploited to identify and potentially target these macrophage subsets in tissue. Furthermore, inducers of regulatory macrophages may have the potential to be used as anti-inflammatory therapeutics. Therefore, a better understanding of the various macrophage phenotypes may pave the way for new therapies that are directed at modulating macrophage functions or manipulating individual macrophage subsets.
    European Journal of Immunology 09/2011; 41(9):2498-502. DOI:10.1002/eji.201141717 · 4.52 Impact Factor
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    ABSTRACT: Leishmania species trigger a brisk inflammatory response and efficiently induce cell-mediated immunity. We examined the mechanisms whereby leukocytes were recruited into lesions after Leishmania major infection of mice. We found that a subpopulation of effector monocytes expressing the granulocyte marker GR1 (Ly6C) is rapidly recruited into lesions, and these monocytes efficiently kill L. major parasites. The recruitment of this subpopulation of monocytes depends on the chemokine receptor CCR2 and the activation of platelets. Activated platelets secrete platelet-derived growth factor, which induces the rapid release of CCL2 from leukocytes and mesenchymal cells. This work points to a new role for platelets in host defense involving the selective recruitment of a subpopulation of effector monocytes from the blood to efficiently kill this intracellular parasite.
    Journal of Experimental Medicine 06/2011; 208(6):1253-65. DOI:10.1084/jem.20101751 · 13.91 Impact Factor
  • Ziyan Yang, Beihua Kong, David M Mosser, Xia Zhang
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    ABSTRACT: Inflammation involves multiple changes in many aspects of immune system. Interactions between immune system and female reproductive system strongly impact fertility and reproductive health in general. Many normal events of female reproduction system including ovulation, menstruation, implantation and labor onset are considered as inflammatory process. Emerging evidence reveals that three components of immune system that are critical to initiate and resolve inflammation, Toll-like receptors (TLRs), macrophages, and natural killer (NK) cells, play important roles not only to provide protection against infections by exogenous pathogens but also to regulate essential functions of uterus and ovary. This review will briefly summarize our understanding of the functions of TLRs, macrophages and NK cells in uterus and ovary.
    International immunopharmacology 05/2011; 11(10):1442-50. DOI:10.1016/j.intimp.2011.04.024 · 2.71 Impact Factor
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    ABSTRACT: The FcγRs found on macrophages (Ms) and dendritic cells (DCs) efficiently facilitate the presentation or cross-presentation of immune-complexed Ags to T cells. We found that the MHC class I-related neonatal FcR for IgG (FcRn) in both Ms and DCs failed to have a strong effect on the cross-presentation of immune complex (IC) OVA Ag to CD8(+) T cells. Interestingly, endosomal FcRn enhanced the presentation of the monomeric OVA-IC to CD4(+) T cells robustly, whereas FcRn in phagosomes exerted distinctive effects on Ag presentation between Ms and DCs. The presentation of phagocytosed OVA-ICs to CD4(+) T cells was considerably enhanced on wild-type versus FcRn-deficient Ms, but was not affected in FcRn-deficient DCs. This functional discrepancy was associated with the dependence of IgG-FcRn binding in an acidic pH. Following phagocytosis, the phagosomal pH dropped rapidly to <6.5 in Ms but remained in the neutral range in DCs. This disparity in pH determined the rate of degradation of phagocytosed ICs. Thus, our findings reveal that FcRn expression has a different effect on Ag processing and presentation of ICs to CD4(+) T cells in the endosomal versus phagosomal compartments of Ms versus DCs.
    The Journal of Immunology 03/2011; 186(8):4674-86. DOI:10.4049/jimmunol.1003584 · 5.36 Impact Factor
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    ABSTRACT: This essay describes how the use of a concept inventory has enhanced professional development and curriculum reform efforts of a faculty teaching community. The Host Pathogen Interactions (HPI) teaching team is composed of research and teaching faculty with expertise in HPI who share the goal of improving the learning experience of students in nine linked undergraduate microbiology courses. To support evidence-based curriculum reform, we administered our HPI Concept Inventory as a pre- and postsurvey to approximately 400 students each year since 2006. The resulting data include student scores as well as their open-ended explanations for distractor choices. The data have enabled us to address curriculum reform goals of 1) reconciling student learning with our expectations, 2) correlating student learning with background variables, 3) understanding student learning across institutions, 4) measuring the effect of teaching techniques on student learning, and 5) demonstrating how our courses collectively form a learning progression. The analysis of the concept inventory data has anchored and deepened the team's discussions of student learning. Reading and discussing students' responses revealed the gap between our understanding and the students' understanding. We provide evidence to support the concept inventory as a tool for assessing student understanding of HPI concepts and faculty development.
    CBE life sciences education 12/2010; 9(4):408-16. DOI:10.1187/cbe.10-05-0069 · 1.88 Impact Factor
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    ABSTRACT: We carried out a model of chronic inflammation using a subcutaneous paraffin tablet in mice experimentally infected with Leishmania major. It was previously reported that the parasite load following paraffin implantation occurred at a peak of 21 days in both BALB/c and C57BL/6 mice. At the present study, we have investigated what cytokines and chemokines are directly related to the parasite load in C57BL/6 mice. All mice were divided in four groups: mice implanted with paraffin tablets; mice experimentally infected with L. major; mice implanted with paraffin tablets and experimentally infected with L. major; and mice submitted only to the surgery were used for the Real-Time Polymerase Chain Reaction (RT-PCR) controls. Fragments of skin tissue and the tissue surrounding the paraffin tablets (inflammatory capsule) were collected for histopathology and RT-PCR studies. By 21 days, a diffuse chronic inflammatory reaction was mainly observed in the deep dermis where macrophages parasitized with Leishmania amastigotes were also found. RT-PCR analysis has shown that BALB/c mice showed strong IL-4 and IL-10 mRNA expression than controls with very little expression of IFN-γ. In contrast, both IFN-γ and IL-10 mRNA was found in higher levels in C57BL/6 animals. Moreover, in C57BL/6 mice the expression of chemokines mRNA of CCL3/MIP-1α was more highly expressed than CCL2/MCP-1. We conclude that the Th1 immune response C57BL/6 did not change to a Th2 response, even though C57BL/6 animals presented higher parasitism than BALB/c mice 21 days after infection and paraffin implantation.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 11/2010; 457(5):609-18. DOI:10.1007/s00428-010-0974-9 · 2.56 Impact Factor
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    Paul Gallo, Ricardo Gonçalves, David M Mosser
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    ABSTRACT: We have previously demonstrated that the addition of immune complexes (IC) to stimulated macrophages could profoundly influence cytokine production. In the present work we sought to determine the density of IgG on immune complexes necessary to mediate phagocytosis, inhibit IL-12 production and induce IL-10 production from stimulated macrophages. We developed immune complexes with predictable average densities of surface-bound immunoglobulin. We show that a threshold amount of IgG was necessary to mediate attachment of IC to macrophages. At progressively higher densities of IgG, Fc receptor-mediated phagocytosis resulted in an inhibition of IL-12 production and then an induction of IL-10. The reciprocal alterations in these two cytokines occurred when as little as one optimally opsonized SRBC was bound per macrophage. Macrophage IL-10 induction by immune complexes was associated with the activation of the MAP kinase, ERK, which was progressively increased as a function of IgG density. We conclude that signal transduction through the macrophage Fcγ receptors vary as a function of signal strength. At moderate IgG densities, especially in the presence of complement, efficient phagocytosis occurs in the absence of cytokine alterations. At slightly higher IgG densities IL-12 production is shut off and eventually IL-10 induction occurs. Thus, the myriad events emanating from FcγR ligation depends on the density of immune complexes, allowing the Fc receptors to fine-tune cellular responses depending on the extent of receptor cross-linking.
    Immunology letters 10/2010; 133(2):70-7. DOI:10.1016/j.imlet.2010.07.004 · 2.37 Impact Factor
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    ABSTRACT: A wide range of microorganisms can replicate in macrophages, and cell entry of these pathogens via non-neutralising IgG antibody complexes can result in increased intracellular infection through idiosyncratic Fcγ-receptor signalling. The activation of Fcγ receptors usually leads to phagocytosis. Paradoxically, the ligation of monocyte or macrophage Fcγ receptors by IgG immune complexes, rather than aiding host defences, can suppress innate immunity, increase production of interleukin 10, and bias T-helper-1 (Th1) responses to Th2 responses, leading to increased infectious output by infected cells. This intrinsic antibody-dependent enhancement (ADE) of infection modulates the severity of diseases as disparate as dengue haemorrhagic fever and leishmaniasis. Intrinsic ADE is distinct from extrinsic ADE, whereby complexes of infectious agents with non-neutralising antibodies lead to an increased number of infected cells. Intrinsic ADE might be involved in many protozoan, bacterial, and viral infections. We review insights into intracellular mechanisms and implications of enhanced pathogenesis after ligation of macrophage Fcγ receptors by infectious immune complexes.
    The Lancet Infectious Diseases 10/2010; 10(10):712-22. DOI:10.1016/S1473-3099(10)70166-3 · 19.45 Impact Factor

Publication Stats

9k Citations
562.45 Total Impact Points

Institutions

  • 2001–2014
    • University of Maryland, College Park
      • Department of Cell Biology & Molecular Genetics
      Maryland, United States
  • 2009–2013
    • Loyola University Maryland
      Baltimore, 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
  • 1991–2001
    • 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
  • 1990
    • New York Medical College
      • Department of Pediatrics
      New York City, NY, United States