Michael B Brenner

Brigham and Women's Hospital, Boston, Massachusetts, United States

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Publications (303)3203.24 Total impact

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    ABSTRACT: Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal binding protein (RBPJ) is a transcriptional repressor but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome wide association studies (GWAS) of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 LD block in human memory, but not in naïve CD4(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4(+) T cells from healthy subjects homozygous for the risk allele (CC) compared to memory CD4(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040(CC) memory T cells showed a repression of canonical Notch target genes IL-9, IL-17 and IFNγ in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while Delta-like 4 (DLL4-Fc), another Notch ligand, induced higher IFNγ expression in the rs874040(CC) memory CD4(+) T cells compared to their rs874040(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared to control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNγ in response to Notch ligation in vitro. These findings demonstrate that the rs874040(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA.
    Human Molecular Genetics 11/2015; DOI:10.1093/hmg/ddv474 · 6.39 Impact Factor
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    ABSTRACT: Semi-invariant/type I NKT cells are a well-characterized CD1d-restricted T cell subset. The availability of potent Ags and tetramers for semi-invariant/type I NKT cells allowed this population to be extensively studied and revealed their central roles in infection, autoimmunity, and tumor immunity. In contrast, diverse/type II NKT (dNKT) cells are poorly understood because the lipid Ags that they recognize are largely unknown. We sought to identify dNKT cell lipid Ag(s) by interrogating a panel of dNKT mouse cell hybridomas with lipid extracts from the pathogen Listeria monocytogenes. We identified Listeria phosphatidylglycerol as a microbial Ag that was significantly more potent than a previously characterized dNKT cell Ag, mammalian phosphatidylglycerol. Further, although mammalian phosphatidylglycerol-loaded CD1d tetramers did not stain dNKT cells, the Listeria-derived phosphatidylglycerol-loaded tetramers did. The structure of Listeria phosphatidylglycerol was distinct from mammalian phosphatidylglycerol because it contained shorter, fully-saturated anteiso fatty acid lipid tails. CD1d-binding lipid-displacement studies revealed that the microbial phosphatidylglycerol Ag binds significantly better to CD1d than do counterparts with the same headgroup. These data reveal a highly potent microbial lipid Ag for a subset of dNKT cells and provide an explanation for its increased Ag potency compared with the mammalian counterpart. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 08/2015; 195(6). DOI:10.4049/jimmunol.1501019 · 4.92 Impact Factor
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    ABSTRACT: Biomarkers are needed to guide treatment decisions for patients with rheumatic diseases. Although the phenotypic and functional analysis of immune cells is an appealing strategy for understanding immune-mediated disease processes, immune cell profiling currently has no role in clinical rheumatology. New technologies, including mass cytometry, gene expression profiling by RNA sequencing (RNA-seq) and multiplexed functional assays, enable the analysis of immune cell function with unprecedented detail and promise not only a deeper understanding of pathogenesis, but also the discovery of novel biomarkers. The large and complex data sets generated by these technologies-big data-require specialized approaches for analysis and visualization of results. Standardization of assays and definition of the range of normal values are additional challenges when translating these novel approaches into clinical practice. In this Review, we discuss technological advances in the high-dimensional analysis of immune cells and consider how these developments might support the discovery of predictive biomarkers to benefit the practice of rheumatology and improve patient care.
    Nature Reviews Rheumatology 06/2015; 11(9). DOI:10.1038/nrrheum.2015.71 · 9.85 Impact Factor
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    ABSTRACT: Engagement of the homotypic cell-to-cell adhesion molecule cadherin-11 on rheumatoid arthritis (RA) synovial fibroblasts with a chimeric molecule containing its extracellular binding domain stimulated cytokine, chemokine, and matrix metalloproteinases (MMP) release, implicating cadherin-11 signaling in RA pathogenesis. The objective of this study was to determine if cadherin-11 extracellular domain fragments are found inside the joint and if a physiologic synovial fibroblast cleavage pathway releases those fragments. Cadherin-11 cleavage fragments were detected by western blot in cell media or lysates. Cleavage was interrupted using chemical inhibitors or short-interfering RNA (siRNA) gene silencing. The amount of cadherin-11 fragments in synovial fluid was measured by western blot and ELISA. Soluble cadherin-11 extracellular fragments were detected in human synovial fluid at significantly higher levels in RA samples compared to osteoarthritis (OA) samples. A cadherin-11 N-terminal extracellular binding domain fragment was shed from synovial fibroblasts after ionomycin stimulation, followed by presenilin 1 (PSN1)-dependent regulated intramembrane proteolysis of the retained membrane-bound C-terminal fragments. In addition to ionomycin-induced calcium flux, tumor necrosis factor (TNF)-α also stimulated cleavage in both two- and three-dimensional fibroblast cultures. Although cadherin-11 extracellular domains were shed by a disintegrin and metalloproteinase (ADAM) 10 in several cell types, a novel ADAM- and metalloproteinase-independent activity mediated shedding in primary human fibroblasts. Cadherin-11 undergoes ectodomain shedding followed by regulated intramembrane proteolysis in synovial fibroblasts, triggered by a novel sheddase that generates extracelluar cadherin-11 fragments. Cadherin-11 fragments were enriched in RA synovial fluid, suggesting they may be a marker of synovial burden and may function to modify cadherin-11 interactions between synovial fibroblasts.
    Arthritis research & therapy 05/2015; 17(1):126. DOI:10.1186/s13075-015-0647-9 · 3.75 Impact Factor
  • Edy Y. Kim · Lydia Lynch · Patrick J. Brennan · Nadia R. Cohen · Michael B. Brenner ·
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    ABSTRACT: Invariant natural killer T (iNKT) cells are innate T cells that express a semi-invariant T cell receptor (TCR) and recognize lipid antigens presented by CD1d molecules. As part of innate immunity, iNKT cells rapidly produce large amounts of cytokines after activation and regulate the function of innate and adaptive immune cells in antimicrobial immunity, tumor rejection and inflammatory diseases. Global transcriptional profiling has advanced our understanding of all aspects of iNKT cell biology. In this review, we discuss transcriptional analyses of iNKT cell development, functional subsets of iNKT cells, and global comparisons of iNKT cells to other innate and adaptive immune cells. Global transcriptional analysis revealed that iNKT cells have a transcriptional profile distinct from NK cells and MHC-restricted T cells, both during thymic development and in the periphery. The transcription factors EGR2 and PLZF (and microRNA like miR-150) are key regulators of the iNKT cell transcriptome during development. PLZF is one of several factors that control the homing and maintenance of organ-specific iNKT cell populations. As in MHC-restricted T cells, specific transcription factors are characteristic of functional subsets of iNKT cells, such as the transcription factor T-bet in the NKT1 subset. Exciting future directions for global transcriptional analyses include iNKT cells in disease models, diverse NKT cells and human studies. Copyright © 2015. Published by Elsevier Ltd.
    Seminars in Immunology 04/2015; 27(1). DOI:10.1016/j.smim.2015.02.005 · 5.17 Impact Factor
  • Salil Garg · Michael B Brenner ·
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    ABSTRACT: Here, we describe the general principles of RNA interference screens to study lysosomal functions in mammalian cells. Lysosomes occupy a central position in the biology of numerous processes such as degradation, microbial killing, and immunological antigen presentation to T cells. Selection of a screening system, conducting pooled versus arrayed screens, and appropriate steps in assay development, validation, and verification of novel gene candidates are all discussed. We focus on our experience in developing an arrayed short hairpin RNA screen to identify novel lysosomal trafficking proteins involved in vesicle and cargo trafficking and illustrate how such a trafficking library can be applied to screens involving lysosomes. Copyright © 2015 Elsevier Inc. All rights reserved.
    Methods in cell biology 02/2015; 126:119-38. DOI:10.1016/bs.mcb.2014.10.030 · 1.42 Impact Factor
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    Raju V V Tatituri · Benjamin J Wolf · Michael B Brenner · John Turk · Fong-Fu Hsu ·
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    ABSTRACT: Listeria monocytogenes (L. monocytogenes) is a facultative, Gram-positive, food-borne bacterium, which causes serious infections. Although it is known that lipids play important roles in the survival of Listeria, the detailed structures of these lipids have not been established. In this contribution, we described linear ion-trap multiple-stage mass spectrometric approaches with high-resolution mass spectrometry toward complete structural analysis including the identities of the fatty acid substituents and their position on the glycerol backbone of the polar lipids, mainly phosphatidylglycerol, cardiolipin (CL), and lysyl-CL from L. monocytogenes. The location of the methyl side group along the fatty acid chain in each lipid family was characterized by a charge-switch strategy. This is achieved by first alkaline hydrolysis to release the fatty acid substituents, followed by tandem mass spectrometry on their N-(4-aminomethylphenyl) pyridinium (AMPP) derivatives as the M+ ions. Several findings in this study are unique: (1) we confirm the presence of a plasmalogen PG family that has not been previous reported; (2) an ion arising from a rare internal loss of lysylglycerol residue was observed in the MS(2) spectrum of lysyl-CL, permitting its distinction from other CL subfamilies.
    Analytical and Bioanalytical Chemistry 02/2015; 407(9). DOI:10.1007/s00216-015-8480-1 · 3.44 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) are specialized APCs with the ability to prime naive T cells. DCs first sample Ags from the environment and then orchestrate their processing and loading onto MHC class II (MHC II) Ag-presenting molecules in lysosomes. Once MHC II molecules have bound a peptide, the MHC II-peptide complex is delivered to the cell surface for presentation to CD4(+) T cells. Regulation of Ag uptake via macropinocytosis and phagocytosis has been extensively studied, as well as trafficking in early endocytic vesicles notably regulated by the small GTPase Rab5 and its effectors. However, little is known about the regulators of Ag delivery from early endosomes to lysosomal compartments where the proper pH, proteases, MHC II, invariant chain, and HLA-DM reside, awaiting exogenous Ags for loading. In this article, we report the crucial role of the small GTPase ADP-ribosylation factor-like 8b (Arl8b) in MHC II presentation in DCs. We show for the first time, to our knowledge, that Arl8b localizes to MHC II compartments in DCs and regulates formation of MHC II-peptide complexes. Arl8b-silenced DCs display a defect in MHC II-Ag complex formation and its delivery to the cell surface during infection resulting in a defect in T cell recognition. Our results highlight the role of Arl8b as a trafficking regulator of the late stage of complex formation and MHC II presentation in DCs. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 01/2015; 194(5). DOI:10.4049/jimmunol.1401072 · 4.92 Impact Factor
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    ABSTRACT: The recognized diversity of innate lymphoid cells (ILCs) is rapidly expanding. Three ILC classes have emerged, ILC1, ILC2 and ILC3, with ILC1 and ILC3 including several subsets. The classification of some subsets is unclear, and it remains controversial whether natural killer (NK) cells and ILC1 cells are distinct cell types. To address these issues, we analyzed gene expression in ILCs and NK cells from mouse small intestine, spleen and liver, as part of the Immunological Genome Project. The results showed unique gene-expression patterns for some ILCs and overlapping patterns for ILC1 cells and NK cells, whereas other ILC subsets remained indistinguishable. We identified a transcriptional program shared by small intestine ILCs and a core ILC signature. We revealed and discuss transcripts that suggest previously unknown functions and developmental paths for ILCs.
    Nature Immunology 01/2015; DOI:10.1038/ni.3094 · 20.00 Impact Factor
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    ABSTRACT: Invariant natural killer T cells (iNKT cells) are lipid-sensing innate T cells that are restricted by the antigen-presenting molecule CD1d and express the transcription factor PLZF. iNKT cells accumulate in adipose tissue, where they are anti-inflammatory, but the factors that contribute to their anti-inflammatory nature, as well as their targets in adipose tissue, are unknown. Here we found that iNKT cells in adipose tissue had a unique transcriptional program and produced interleukin 2 (IL-2) and IL-10. Unlike other iNKT cells, they lacked PLZF but expressed the transcription factor E4BP4, which controlled their IL-10 production. The adipose iNKT cells were a tissue-resident population that induced an anti-inflammatory phenotype in macrophages and, through the production of IL-2, controlled the number, proliferation and suppressor function of regulatory T cells (Treg cells) in adipose tissue. Thus, iNKT cells in adipose tissue are unique regulators of immunological homeostasis in this tissue.
    Nature Immunology 12/2014; 16(1). DOI:10.1038/ni.3047 · 20.00 Impact Factor

  • Biomedical Engineering Society Annual Conference. 2014.; 10/2014
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    ABSTRACT: As part of the Immunological Genome Project (ImmGen), gene expression was determined in unstimulated (circulating) mouse neutrophils and three populations of neutrophils activated in vivo, with comparison among these populations and to other leukocytes. Activation conditions included serum-transfer arthritis (mediated by immune complexes), thioglycollate-induced peritonitis, and uric acid-induced peritonitis. Neutrophils expressed fewer genes than any other leukocyte population studied in ImmGen, and down-regulation of genes related to translation was particularly striking. However, genes with expression relatively specific to neutrophils were also identified, particularly three genes of unknown function: Stfa2l1, Mrgpr2a and Mrgpr2b. Comparison of genes up-regulated in activated neutrophils led to several novel findings: increased expression of genes related to synthesis and use of glutathione and of genes related to uptake and metabolism of modified lipoproteins, particularly in neutrophils elicited by thioglycollate; increased expression of genes for transcription factors in the Nr4a family, only in neutrophils elicited by serum-transfer arthritis; and increased expression of genes important in synthesis of prostaglandins and response to leukotrienes, particularly in neutrophils elicited by uric acid. Up-regulation of genes related to apoptosis, response to microbial products, NFkB family members and their regulators, and MHC class II expression was also seen, in agreement with previous studies. A regulatory model developed from the ImmGen data was used to infer regulatory genes involved in the changes in gene expression during neutrophil activation. Among 64, mostly novel, regulatory genes predicted to influence these changes in gene expression, Irf5 was shown to be important for optimal secretion of IL-10, IP-10, MIP-1α, MIP-1β, and TNF-α by mouse neutrophils in vitro after stimulation through TLR9. This data-set and its analysis using the ImmGen regulatory model provide a basis for additional hypothesis-based research on the importance of changes in gene expression in neutrophils in different conditions.
    PLoS ONE 10/2014; 9(10):e108553. DOI:10.1371/journal.pone.0108553. · 3.23 Impact Factor
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    ABSTRACT: Abstract To determine the breadth and underpinning of changes in immunocyte gene expression due to genetic variation in mice, we performed, as part of the Immunological Genome Project, gene expression profiling for CD4+ T cells and neutrophils purified from 39 inbred strains of the Mouse Phenome Database. Considering both cell types, a large number of transcripts showed significant variation across the inbred strains, with 22% of the transcriptome varying by 2-fold or more. These included 119 loci with apparent complete loss of function, where the corresponding transcript was not expressed in some of the strains, representing a useful resource of "natural knockouts." We identified 1222 cis-expression quantitative trait loci (cis-eQTL) that control some of this variation. Most (60%) cis-eQTLs were shared between T cells and neutrophils, but a significant portion uniquely impacted one of the cell types, suggesting cell type-specific regulatory mechanisms. Using a conditional regression algorithm, we predicted regulatory interactions between transcription factors and potential targets, and we demonstrated that these predictions overlap with regulatory interactions inferred from transcriptional changes during immunocyte differentiation. Finally, comparison of these and parallel data from CD4+ T cells of healthy humans demonstrated intriguing similarities in variability of a gene's expression: the most variable genes tended to be the same in both species, and there was an overlap in genes subject to strong cis-acting genetic variants. We speculate that this "conservation of variation" reflects a differential constraint on intraspecies variation in expression levels of different genes, either through lower pressure for some genes, or by favoring variability for others.
    The Journal of Immunology 09/2014; 193(9). DOI:10.4049/jimmunol.1401280 · 4.92 Impact Factor
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    ABSTRACT: Invariant natural killer T (iNKT) cells are a specialized T-cell subset that recognizes lipids as antigens, contributing to immune responses in diverse disease processes. Experimental data suggests that iNKT cells can recognize both microbial and endogenous lipid antigens. Several candidate endogenous lipid antigens have been proposed, although the contextual role of specific antigens during immune responses remains largely unknown. We have previously reported that mammalian glucosylceramides (GlcCers) activate iNKT cells. GlcCers are found in most mammalian tissues, and exist in variable molecular forms that differ mainly in N-acyl fatty acid chain use. In this report, we purified, characterized, and tested the GlcCer fractions from multiple animal species. Although activity was broadly identified in these GlcCer fractions from mammalian sources, we also found activity properties that could not be reconciled by differences in fatty acid chain use. Enzymatic digestion of β-GlcCer and a chromatographic separation method demonstrated that the activity in the GlcCer fraction was limited to a rare component of this fraction, and was not contained within the bulk of β-GlcCer molecular species. Our data suggest that a minor lipid species that copurifies with β-GlcCer in mammals functions as a lipid self antigen for iNKT cells.
    Proceedings of the National Academy of Sciences 09/2014; 111(37). DOI:10.1073/pnas.1415357111 · 9.67 Impact Factor
  • Steven Porcelli · Courtland E Yockey · Michael B Brenner · Steven P Balk ·
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    ABSTRACT: CD4 CD8 (double negative [ON]) α/β T cells are a largely uncharacterized subpopulation of unknown function. To investigate whether these cells are selected to recognize particular antigens or antigen-presenting molecules, ON α/β T cells were purified from the peripheral blood of five normal donors and their T cell receptor (TCR) a and fi chains were examined. Random cloning of TCR a chains by single-sided polymerase chain reaction (PCR) amplification identified an invariant rearrangement between Va24 and JaQ, with no N region diversity, which was expressed preferentially by DN α/β T cells from all donors. Random cloning also identified a precise Va7.2-Ja(IGRJa14) rearrangement, with two variable amino acids encoded in the V-J junction, which was enriched in the ON α/β T cell preparations from some, but not all, donors. Analysis of TCR β chains by quantitative PCR. amplification demonstrated that the expression of four Vfl gene families, Vβ, 8, 11, and 13, was markedly increased in these ON α/β T cell preparations. The expression of particular TCRs by ON α/β T cells from multiple donors indicates that these cells, or at least a subpopulation of cells with this phenotype, recognize a limited spectrum of antigens and suggests that they may use nonpolymorphic antigen-presenting molecules.
    The Journal of Immunology 08/2014; 193(3):977-92. · 4.92 Impact Factor
  • Zhizhan Gu · Jian Li · Elina A. Tonkova · Soo Young Lee · Victor W. Hsu · Michael B. Brenner ·

    Gordon Research Conference - Signaling By Adhesion Receptors. 2014.; 06/2014
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    ABSTRACT: Invariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8(+) T and NK cells. Although iNKT cells thereby act as potent cellular adjuvants, it is less clear whether they directly control the growth of tumors. To gain insights into the direct contribution of iNKT cells to tumor immune surveillance, we developed in vitro and in vivo systems to selectively examine the antitumor activity of iNKT cells in the absence of other cytolytic effectors. Using the EL4 T-lymphoma cell line as a model, we find that iNKT cells exert robust and specific lysis of tumor cells in vitro in a manner that is differentially-induced by iNKT cell agonists of varying TCR affinities, such as OCH, α-galactosyl ceramide and PBS44. In vitro blockade of CD1d-mediated lipid antigen presentation, disruption of T cell receptor (TCR) signaling, or loss of perforin expression significantly reduce iNKT cell killing. Consistent with these findings, iNKT cell reconstitution of T, B, and NK cell-deficient mice slows EL4 growth in vivo via TCR-CD1d and perforin-dependent mechanisms. Together, these observations establish that iNKT cells are sufficient to control the growth of T-lymphoma in vitro and in vivo. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d(+) cancers, such as T-lymphoma.
    06/2014; 2(1):59-69. DOI:10.1158/2326-6066.CIR-13-0104
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    ABSTRACT: Genome-wide association studies (GWAS) and subsequent dense-genotyping of associated loci identified over a hundred single-nucleotide polymorphism (SNP) variants associated with the risk of rheumatoid arthritis (RA), type 1 diabetes (T1D), and celiac disease (CeD). Immunological and genetic studies suggest a role for CD4-positive effector memory T (CD+ TEM) cells in the pathogenesis of these diseases. To elucidate mechanisms of autoimmune disease alleles, we investigated molecular phenotypes in CD4+ effector memory T cells potentially affected by these variants. In a cohort of genotyped healthy individuals, we isolated high purity CD4+ TEM cells from peripheral blood, then assayed relative abundance, proliferation upon T cell receptor (TCR) stimulation, and the transcription of 215 genes within disease loci before and after stimulation. We identified 46 genes regulated by cis-acting expression quantitative trait loci (eQTL), the majority of which we detected in stimulated cells. Eleven of the 46 genes with eQTLs were previously undetected in peripheral blood mononuclear cells. Of 96 risk alleles of RA, T1D, and/or CeD in densely genotyped loci, eleven overlapped cis-eQTLs, of which five alleles completely explained the respective signals. A non-coding variant, rs389862A, increased proliferative response (p = 4.75×10-8). In addition, baseline expression of seventeen genes in resting cells reliably predicted proliferative response after TCR stimulation. Strikingly, however, there was no evidence that risk alleles modulated CD4+ TEM abundance or proliferation. Our study underscores the power of examining molecular phenotypes in relevant cells and conditions for understanding pathogenic mechanisms of disease variants.
    PLoS Genetics 06/2014; 10(6):e1004404. DOI:10.1371/journal.pgen.1004404 · 7.53 Impact Factor
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    ABSTRACT: Systemic sclerosis (SSc) is a chronic autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Recent microarray studies demonstrated that cadherin 11 (Cad-11) expression is increased in the affected skin of patients with SSc. The purpose of this study was to examine our hypothesis that Cad-11 is a mediator of dermal fibrosis. Biopsy samples of skin from SSc patients and healthy control subjects were used for real-time quantitative polymerase chain reaction analysis to assess Cad-11 expression and for immunohistochemistry to determine the expression pattern of Cad-11. To determine whether Cad-11 is a mediator of dermal fibrosis, Cad-11-deficient mice and anti-Cad-11 monoclonal antibodies (mAb) were used in the bleomycin-induced dermal fibrosis model. In vitro studies with dermal fibroblasts and bone marrow-derived macrophages were used to determine the mechanisms by which Cad-11 contributes to the development of tissue fibrosis. Levels of messenger RNA for Cad-11 were increased in skin biopsy samples from patients with SSc and correlated with the modified Rodnan skin thickness scores. Cad-11 expression was localized to dermal fibroblasts and macrophages in SSc skin. Cad-11-knockout mice injected with bleomycin had markedly attenuated dermal fibrosis, as quantified by measurements of skin thickness, collagen levels, myofibroblast accumulation, and profibrotic gene expression, in lesional skin as compared to the skin of wild-type mice. In addition, anti-Cad-11 mAb decreased fibrosis at various time points in the bleomycin-induced dermal fibrosis model. In vitro studies demonstrated that Cad-11 regulated the production of transforming growth factor β (TGFβ) by macrophages and the migration of fibroblasts. These data demonstrate that Cad-11 is a mediator of dermal fibrosis and TGFβ production and suggest that Cad-11 may be a therapeutic target in SSc.
    Arthritis and Rheumatology 04/2014; 66(4):1010-21. DOI:10.1002/art.38275
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    ABSTRACT: Directional mesenchymal cell invasion in vivo is understood to be a stimulated event and to be regulated by cytokines, chemokines and types of extracellular matrix (ECM). Instead, by focusing on the cellular response to ECM stiffness, we found that soft ECM (low stiffness) itself is sufficient to prevent stable cell-to-cell adherens junction (AJ) formation, up-regulate MMP secretion, promote MMP activity and induce invadosome-like protrusion (ILP) formation. Consistently, similar ILP formation was also detected in a 3D directional invasion assay in soft matrix. Primary human fibroblasts spontaneously form ILPs in a very narrow range of ECM stiffness (0.1 ∼ 0.4 kPa) and such ILP formation is Src family kinase (SFK) dependent. In contrast, spontaneous ILP formation in malignant cancer cells and fibrosarcoma cells occurs across a much wider range of ECM stiffness, and these tumor cell ILPs are also more prominent at lower stiffness. These findings suggest that ECM softness is a natural stimulator for cellular invasiveness.
    Molecular biology of the cell 12/2013; 25(4). DOI:10.1091/mbc.E13-05-0260 · 4.47 Impact Factor

Publication Stats

28k Citations
3,203.24 Total Impact Points


  • 1992-2015
    • Brigham and Women's Hospital
      • • Division of Rheumatology, Immunology, and Allergy
      • • Department of Medicine
      • • Lymphocyte Biology Section
      Boston, Massachusetts, United States
  • 1987-2015
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, Massachusetts, United States
  • 1988-2014
    • Stanford University
      • • Department of Computer Science
      • • Department of Pathology
      Palo Alto, California, United States
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Parasitic Diseases (LPD)
      Maryland, United States
    • Stanford Medicine
      • Department of Pathology
      Stanford, California, United States
  • 2013
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
  • 2012
    • Aarhus University
      Aarhus, Central Jutland, Denmark
  • 2008
    • University of Birmingham
      • School of Biosciences
      Birmingham, England, United Kingdom
  • 1985-2007
    • Dana-Farber Cancer Institute
      • • Department of Medical Oncology
      • • Department of Cancer Immunology and AIDS
      Boston, Massachusetts, United States
  • 2003
    • Boston University
      • Department of Biochemistry
      Boston, Massachusetts, United States
  • 2000
    • Lund University
      Lund, Skåne, Sweden
  • 1999
    • University of Illinois at Chicago
      Chicago, Illinois, United States
    • The Scripps Research Institute
      لا هویا, California, United States
  • 1995
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1993
    • Leukemia & Lymphoma Society
      Society Hill, New Jersey, United States

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