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Liu H, Jakubzick C, Osterburg AR, Nelson RL, Gupta N, McCormack FX, Borchers MT. Dendritic Cell Trafficking and Function in Rare Lung Diseases. Am J Respir Cell Mol Biol 2017; 57:393-402. [PMID: 28586276 PMCID: PMC5650088 DOI: 10.1165/rcmb.2017-0051ps] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 06/06/2017] [Indexed: 12/14/2022] Open
Abstract
Dendritic cells (DCs) are highly specialized immune cells that capture antigens and then migrate to lymphoid tissue and present antigen to T cells. This critical function of DCs is well defined, and recent studies further demonstrate that DCs are also key regulators of several innate immune responses. Studies focused on the roles of DCs in the pathogenesis of common lung diseases, such as asthma, infection, and cancer, have traditionally driven our mechanistic understanding of pulmonary DC biology. The emerging development of novel DC reagents, techniques, and genetically modified animal models has provided abundant data revealing distinct populations of DCs in the lung, and allow us to examine mechanisms of DC development, migration, and function in pulmonary disease with unprecedented detail. This enhanced understanding of DCs permits the examination of the potential role of DCs in diseases with known or suspected immunological underpinnings. Recent advances in the study of rare lung diseases, including pulmonary Langerhans cell histiocytosis, sarcoidosis, hypersensitivity pneumonitis, and pulmonary fibrosis, reveal expanding potential pathogenic roles for DCs. Here, we provide a review of DC development, trafficking, and effector functions in the lung, and discuss how alterations in these DC pathways contribute to the pathogenesis of rare lung diseases.
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Affiliation(s)
- Huan Liu
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Claudia Jakubzick
- Department of Immunology and Microbiology, National Jewish Health and University of Colorado, Denver, Colorado; and
| | - Andrew R. Osterburg
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Rebecca L. Nelson
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Nishant Gupta
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio
- Cincinnati Veteran’s Affairs Medical Center, Cincinnati, Ohio
| | - Francis X. McCormack
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio
- Cincinnati Veteran’s Affairs Medical Center, Cincinnati, Ohio
| | - Michael T. Borchers
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio
- Cincinnati Veteran’s Affairs Medical Center, Cincinnati, Ohio
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2
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Teoh CM, Tan SSL, Tran T. Integrins as Therapeutic Targets for Respiratory Diseases. Curr Mol Med 2016; 15:714-34. [PMID: 26391549 PMCID: PMC5427774 DOI: 10.2174/1566524015666150921105339] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 09/09/2015] [Accepted: 09/19/2015] [Indexed: 01/14/2023]
Abstract
Integrins are a large family of transmembrane heterodimeric proteins that constitute the main receptors for extracellular matrix components. Integrins were initially thought to be primarily involved in the maintenance of cell adhesion and tissue integrity. However, it is now appreciated that integrins play important roles in many other biological processes such as cell survival, proliferation, differentiation, migration, cell shape and polarity. Lung cells express numerous combinations and permutations of integrin heterodimers. The complexity and diversity of different integrin heterodimers being implicated in different lung diseases present a major challenge for drug development. Here we provide a comprehensive overview of the current knowledge of integrins from studies in cell culture to integrin knockout mouse models and provide an update of results from clinical trials for which integrins are therapeutic targets with a focus on respiratory diseases (asthma, emphysema, pneumonia, lung cancer, pulmonary fibrosis and sarcoidosis).
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Affiliation(s)
| | | | - T Tran
- Department of Physiology, MD9, 2 Medical Drive, National University of Singapore, Singapore 117597, Singapore.
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3
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van Tongeren J, Reinartz SM, Fokkens WJ, de Jong EC, van Drunen CM. Interactions between epithelial cells and dendritic cells in airway immune responses: lessons from allergic airway disease. Allergy 2008; 63:1124-35. [PMID: 18699930 DOI: 10.1111/j.1398-9995.2008.01791.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Micro-organisms constantly invade the human body and may form a threat to our health. Traditionally, concepts of defence mechanisms have included a protective outer layer of epithelia and a vigilant immune system searching for areas where the integrity of the outer layer may be compromised. Instead of considering these elements as two independent mechanisms, we should be treating them as a single integrated system. This review will present and discuss the role of local immune-competent cells and local epithelia in the recognition of potential pathogens and how the interaction between the two components may affect the initiation of the airway immune response. A concept emerges where airway mucosal dendritic cells act as integrators of both immunostimulatory and immunosuppressive signals that act within actively-involved mucosal tissue.
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Affiliation(s)
- J van Tongeren
- Department of Otorhinolaryngology, Academic Medical Centre, Amsterdam, The Neitherlands
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4
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Obermajer N, Svajger U, Bogyo M, Jeras M, Kos J. Maturation of dendritic cells depends on proteolytic cleavage by cathepsin X. J Leukoc Biol 2008; 84:1306-15. [PMID: 18701767 DOI: 10.1189/jlb.0508285] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
The maturation status of dendritic cells (DCs) is crucial for effective antigen presentation and initiation of the primary immune response. Maturation stimuli cause the adhesion of immature DCs to the extracellular matrix, which is accompanied by recruitment of the CD11b/CD18 [macrophage antigen-1 (Mac-1)] integrin receptor, cytoskeleton reorganization, and podosome formation. Cathepsin X, a cysteine protease expressed in DCs and other APCs, is involved in Mac-1 activation. We have shown that during maturation, cathepsin X translocates to the plasma membrane of maturing DCs, enabling Mac-1 activation and consequently, cell adhesion. In mature DCs, cathepsin X redistributes from the membrane to the perinuclear region, which coincides with the de-adhesion of DCs, formation of cell clusters, and acquisition of the mature phenotype. Inhibition of cathepsin X activity during DC differentiation and maturation resulted in an altered phenotype and function of mature DCs. It reduced surface expression of costimulatory molecules, increased expression of inhibitory Ig-like transcripts 3 and 4 (ILT3 and ILT4), almost completely abolished cytokine production, diminished migration, and reduced the capacity of DCs to stimulate T lymphocytes. These results stress the importance of cathepsin X in regulating DC adhesion, a crucial event for their maturation and T cell activation.
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McGill J, Van Rooijen N, Legge KL. Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs. ACTA ACUST UNITED AC 2008; 205:1635-46. [PMID: 18591411 PMCID: PMC2442641 DOI: 10.1084/jem.20080314] [Citation(s) in RCA: 191] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Influenza infections induce a rapid, but transient, dendritic cell (DC) migration from the lungs to the lymph nodes (LNs) that is followed by substantial recruitment of DCs into the lungs without subsequent migration to the LNs. Given that peripheral DCs are primarily thought to be involved in the initiation of adaptive immunity after migration into lymphoid tissues, what role these newly lung-recruited DCs play in influenza virus immunity is unclear. In this study, we demonstrate that loss of non-LN migratory pulmonary DC subsets increases mortality, sustains higher viral titers, and impairs pulmonary CD8 T cell responses. Reconstitution of the lungs with pulmonary plasmacytoid DCs, CD8α+ DCs, or interstitial DCs restores CD8 T cell responses in a cell contact–, major histocompatability complex I–, and influenza peptide–dependent manner. Thus, after their initial activation in the LN, protective influenza-specific CD8 T cell responses require additional antigen-dependent interactions, specifically with DCs in the lungs.
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Affiliation(s)
- Jodi McGill
- Department of Pathology, Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52241, USA
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6
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Wethmar K, Helmus Y, Lühn K, Jones C, Laskowska A, Varga G, Grabbe S, Lyck R, Engelhardt B, Bixel MG, Butz S, Loser K, Beissert S, Ipe U, Vestweber D, Wild MK. Migration of immature mouse DC across resting endothelium is mediated by ICAM-2 but independent of beta2-integrins and murine DC-SIGN homologues. Eur J Immunol 2006; 36:2781-94. [PMID: 16981228 DOI: 10.1002/eji.200526311] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Immature dendritic cells (DC) reside in tissues where they initiate immune responses by taking up foreign antigens. Since DC have a limited tissue half-life, the DC pool in tissues has to be replenished constantly. This implies that precursor/immature DC must be able to cross non-activated endothelium using as yet unknown mechanisms. Here we show that immature, but not mature bone marrow-derived murine DC migrate across resting endothelial monolayers in vitro. We find that endothelial intercellular adhesion molecule-2 (ICAM-2) is a major player in transendothelial migration (TEM) of immature DC, accounting for at least 41% of TEM. Surprisingly, the ICAM-2-mediated TEM was independent of beta2-integrins, the known ICAM-2 ligands, since neither blocking of beta2-integrins with antibodies nor the use of CD18-deficient DC affected the ICAM-2-specific TEM. In humans, the C-type lectin DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN) was shown to interact with ICAM-2, suggesting a similar role in mice. However, we find that none of the murine DC-SIGN homologues mDC-SIGN, murine DC-SIGN-related molecule-1 (mSIGN-R1) and mSIGN-R3 is expressed on the surface of bone marrow-derived mouse DC. Taken together, this study shows that ICAM-2 strongly supports transmigration of immature DC across resting endothelium by interacting with ligands that are distinct from beta2-integrins and DC-SIGN homologues.
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Affiliation(s)
- Klaus Wethmar
- Max Planck Institute for Molecular Biomedicine, Münster, Germany, and Institute of Cell Biology, ZMBE, University of Münster, Münster, Germany
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Burns S, Hardy SJ, Buddle J, Yong KL, Jones GE, Thrasher AJ. Maturation of DC is associated with changes in motile characteristics and adherence. ACTA ACUST UNITED AC 2004; 57:118-32. [PMID: 14691951 DOI: 10.1002/cm.10163] [Citation(s) in RCA: 130] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Migration of dendritic cells (DC) from sentinel sites to lymphoid tissue entails the initiation and coordination of a complex series of cytoskeletal rearrangements resulting in polarised protrusion, formation of new adhesion points, and detachment. Although many diverse receptor-ligand interactions stimulating DC maturation and migration have been identified, the changes that occur in the structure of the actin cytoskeleton during these processes have received little attention. When derived in vitro, immature DC floated in clumps, and upon addition of maturation stimuli such as lipopolysaccharide (LPS), they rapidly adhered, developed polarity, and assembled actin-rich structures known as podosomes at the leading edge of the cell. Podosome assembly was associated with the specific recruitment of beta2 integrins, which in the absence of the Wiskott Aldrich Syndrome protein (WASp), did not occur. As maturation progressed, normal DC once again became rounded and devoid of podosomes. This change in morphology was closely associated with a quantitatively reduced ability to adhere to fibronectin or ICAM-1-coated surfaces. In immature DC, failure to form podosomes or selective inhibition of the CD18 component of podosomes resulted in a similarly reduced ability to adhere to ICAM-1, indicating that podosomes, through CD18, are necessary for tight adhesion to this ligand. We, therefore, propose that podosomes provide an essential link between directional cell protrusion and achievement of DC translocation by establishing new dynamic anchor points at the front of the cell. The temporal regulation of podosome assembly during DC maturation also suggests that they may be most critical for early movement, perhaps during transmigration of lymphatic endothelium.
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Affiliation(s)
- Siobhan Burns
- Molecular Immunology Unit, Institute of Child Health, University College London, 30 Guilford Street, London, United Kingdom.
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8
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Katagiri K, Ohnishi N, Kabashima K, Iyoda T, Takeda N, Shinkai Y, Inaba K, Kinashi T. Crucial functions of the Rap1 effector molecule RAPL in lymphocyte and dendritic cell trafficking. Nat Immunol 2004; 5:1045-51. [PMID: 15361866 DOI: 10.1038/ni1111] [Citation(s) in RCA: 150] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2004] [Accepted: 08/06/2004] [Indexed: 01/19/2023]
Abstract
Immunosurveillance requires the coordinated regulation of chemokines and adhesion molecules to guide immune cell migration. However, the critical molecule for governing the high trafficking capability of immune cells is not clear. Here we show that the effector molecule RAPL is indispensable in the integrin-mediated adhesion and migration of lymphocytes and dendritic cells. RAPL deficiency caused defective chemokine-triggered lymphocyte adhesion and migration to secondary lymphoid organs, resulting in atrophic lymphoid follicles and deficient marginal zone B cells, concomitant with increased immature B cells in the blood. Furthermore, splenic dendritic cells were diminished and defective in adhesion. After being activated with inflammatory stimuli, skin and splenic dendritic cells failed to migrate into either the draining lymph nodes or the white pulp of the spleen. Thus, RAPL is a crucial immune cell trafficking regulator essential for immunosurveillance.
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Affiliation(s)
- Koko Katagiri
- Department of Molecular Immunology and Allergy, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
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9
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Guo SM, Tong HB, Bai LS, Yang W. Effect of traditional Chinese medicinal enemas on ulcerative colitis of rats. World J Gastroenterol 2004; 10:1914-7. [PMID: 15222036 PMCID: PMC4572230 DOI: 10.3748/wjg.v10.i13.1914] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the effects of traditional Chinese medicinal enema (TCME) on inflammatory and immune response of colonic mucosa of rats with ulcerative colitis (UC), and to observe the pathogenic mechanism.
METHODS: Thirty UC rats, induced by intestinal enema together with 2.4-dinitrochlorobenzene (DNCB) and acetic acid, were randomly divided into 3 groups, i.e., G I, G II and G III. Groups G I and G II were administered with TCME and salazosulfapyridine enema (SASPE), respectively. Group G III was clystered with only normal saline (NSE), served as control. Group G IV was taken from normal rats as reference, once daily, from the 7th day after the establishment of UC for total 28 d. Interleukin-6 (IL-6) in the colonic mucosa was assayed by 3H-TdR incorporation assay. Colonic mucosal lymphocyte subpopulation adhesive molecules, CD4+CD11a+, CD4+CD18+, CD8+CD11a+, CD8+CD18+ (LSAM), tumor necrosis factor (TNF)-α, and interferon-γ (IFN-γ), were detected by enzyme linked immunosorbent assay (ELISA). Moreover, the expression of TNF-α mRNA and IFN-γ mRNA in colonic mucosa were detected by polymerase chain reaction (RT-PCR).
RESULTS: Before therapies, in model groups, G I, G II and G III, levels of IL-6, TNF-α, IFN-γ, CD8+CD11a+ and CD8+CD18+ were significantly different (38.29 ± 2.61 U/mL, 16.54 ± 1.23 ng/L, 8.61 ± 0.89 ng/L, 13.51% ± 2.31% and 12.22% ± 1.13%, respectively) compared to those in G IV group (31.56 ± 2.47 U/mL, 12.81 ± 1.38 ng/L, 5.28 ± 0.56 ng/L, 16.68% ± 1.41% and 16.79% ± 1.11%, respectively). After therapeutic enemas, in G I group, the contents of IL-6 (32.48 ± 2.53 U/m), TNF-α (13.42 ± 1.57 ng/L) and IFN-γ (5.87 ± 0.84 ng/L) were reduced; then, the contents of CD8+CD11a+ (16.01% ± 1.05 %) and CD8+CD18+ (16.28% ± 0.19%) were raised. There was no significant difference between groups G I and G IV, but the difference between groups G I and G II was quite obvious (P < 0.05). The expressions of TNF-α mRNA and IFN-γ mRNA in group G III were much higher than those of group G IV, but those in group G I were significantly suppressed by TCME therapy.
CONCLUSION: Ulcerative colitis is related to colonic regional mucosal inflammatory factors and immune imbalance. TCME can effectively inhibit regional mucosal inflammatory factors and improve their disorder of immunity.
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Affiliation(s)
- Song-Ming Guo
- Department of Traditional Chinese Medicine, Tongji Hospital, Tongji University, Shanghai 200065, China.
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10
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Imhof BA, Aurrand-Lions M. Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol 2004; 4:432-44. [PMID: 15173832 DOI: 10.1038/nri1375] [Citation(s) in RCA: 377] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Beat A Imhof
- Centre Medical Universitaire, Department of Pathology and Immunology, 1 Rue Michel-Servet, 1204, Geneva, Switzerland.
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11
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Pribila JT, Itano AA, Mueller KL, Shimizu Y. The alpha 1 beta 1 and alpha E beta 7 integrins define a subset of dendritic cells in peripheral lymph nodes with unique adhesive and antigen uptake properties. THE JOURNAL OF IMMUNOLOGY 2004; 172:282-91. [PMID: 14688336 DOI: 10.4049/jimmunol.172.1.282] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Dendritic cells (DCs) are a heterogeneous population of APCs with critical roles in T cell activation and immune regulation. We report in this study the identification and characterization of a novel subset of DCs resident in skin-draining peripheral lymph nodes of normal mice. This subset of CD11c(high)CD40(high)CD8alpha(intermediate (int)) DCs expresses the collagen-binding integrin, alpha1beta1, and the E-cadherin-binding integrin, alphaEbeta7. Although alpha1beta1 and alphaEbeta7 are also expressed on CD11c(high)CD40(int)CD8alpha(high) lymphoid DCs, CD11c(high)CD40(high)CD8alpha(int) DCs demonstrate preferential integrin-mediated adhesion to collagen and fibronectin. This DC subset most likely acquires expression of these integrins in peripheral lymph node, as this subset is not found in the spleen or mesenteric lymph node, and recent DC migrants from the skin lack expression of alpha1beta1 and alphaEbeta7 integrins. Resident CD40(high) DCs express alpha1beta1 integrin and colocalize with collagen in lymph nodes. When compared with CD11c(high)CD40(high)CD8alpha(int) DCs lacking expression of these integrins, the alpha1beta1+alphaEbeta7+DC subset exhibits more efficient formation of Ag-independent conjugates with T cells, and a decreased ability to acquire soluble Ag. Thus, the alpha1beta1 and alphaEbeta7 integrins define a unique population of peripheral lymph node-derived DCs with altered functional properties and adhesive potential that localizes these cells to sites in lymph nodes where Ag presentation to T cells occurs.
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Affiliation(s)
- Jonathan T Pribila
- Department of Laboratory Medicine and Pathology, Center for Immunology, Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA
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12
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Fainaru O, Woolf E, Lotem J, Yarmus M, Brenner O, Goldenberg D, Negreanu V, Bernstein Y, Levanon D, Jung S, Groner Y. Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation. EMBO J 2004; 23:969-79. [PMID: 14765120 PMCID: PMC380997 DOI: 10.1038/sj.emboj.7600085] [Citation(s) in RCA: 232] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2003] [Accepted: 12/18/2003] [Indexed: 11/09/2022] Open
Abstract
Runx3 transcription factor regulates cell lineage decisions in thymopoiesis and neurogenesis. Here we report that Runx3 knockout (KO) mice develop spontaneous eosinophilic lung inflammation associated with airway remodeling and mucus hypersecretion. Runx3 is specifically expressed in mature dendritic cells (DC) and mediates their response to TGF-beta. In the absence of Runx3, DC become insensitive to TGF-beta-induced maturation inhibition, and TGF-beta-dependent Langerhans cell development is impaired. Maturation of Runx3 KO DC is accelerated and accompanied by increased efficacy to stimulate T cells and aberrant expression of beta2-integrins. Lung alveoli of Runx3 KO mice accumulate DC characteristic of allergic airway inflammation. Taken together, abnormalities in DC function and subset distribution may constitute the primary immune system defect, which leads to the eosinophilic lung inflammation in Runx3 KO mice. These data may help elucidate the molecular mechanisms underlying the pathogenesis of allergic airway inflammation in humans.
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Affiliation(s)
- Ofer Fainaru
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
| | - Eilon Woolf
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
| | - Joseph Lotem
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
| | - Merav Yarmus
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
| | - Ori Brenner
- Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot, Israel
| | - Dalia Goldenberg
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
| | - Varda Negreanu
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
| | - Yael Bernstein
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
| | - Ditsa Levanon
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
| | - Steffen Jung
- Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
| | - Yoram Groner
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: +972 8 934 3972; Fax: +972 8 934 4108; E-mail:
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13
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Ichiyasu H, McCormack JM, McCarthy KM, Dombkowski D, Preffer FI, Schneeberger EE. Matrix metalloproteinase-9-deficient dendritic cells have impaired migration through tracheal epithelial tight junctions. Am J Respir Cell Mol Biol 2003; 30:761-70. [PMID: 14656746 DOI: 10.1165/rcmb.2003-0370oc] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
When sampling inhaled antigens, dendritic cells (DC) must penetrate the tight junction (TJ) barrier while maintaining the TJ seal. In matrix metalloproteinase (MMP)-9-deficient mice, in vivo experiments suggest that migration of DC into air spaces is impaired. To examine the underlying mechanisms, we established a well-defined in vitro model using mouse tracheal epithelial cells and mouse bone marrow DC (BMDC). Transmigration was elicited with either macrophage inflammatory protein (MIP)-1alpha or MIP-3beta in a time-dependent manner. Control MMP-9(+/+) BMDC cultured with granulocyte macrophage-colony-stimulating factor for 7 d showed a 30-fold greater transepithelial migration toward MIP-3beta than MIP-1alpha, indicating a more mature DC phenotype. MMP-9(-/-) BMDC as well as MMP-9(+/+) BMDC in the presence of the MMP inhibitor GM6001, although showing a similar preference for MIP-3beta, were markedly impaired in their ability to traverse the epithelium. Expression levels of CCR5 and CCR7, however, were similar in both MMP-9(-/-) and MMP-9(+/+) BMDC. Expression of the integral TJ proteins, occludin and claudin-1, were examined in BMDC before and after transepithelial migration. Interestingly, occludin but not claudin-1 was degraded following transepithelial migration in both MMP-9(-/-) and control BMDC. In addition, there was a > 2-fold increase in claudin-1 expression in MMP-9(-/-) as compared with control BMDC. These observations indicate that occludin and claudin-1 are differentially regulated and suggest that the lack of MMP-9 may affect claudin-1 turnover.
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Affiliation(s)
- Hidenori Ichiyasu
- Molecular Pathology Unit, Department of Pathology, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA
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14
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Mollà M, Gironella M, Miquel R, Tovar V, Engel P, Biete A, Piqué JM, Panés J. Relative roles of ICAM-1 and VCAM-1 in the pathogenesis of experimental radiation-induced intestinal inflammation. Int J Radiat Oncol Biol Phys 2003; 57:264-73. [PMID: 12909242 DOI: 10.1016/s0360-3016(03)00523-6] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE Cell adhesion molecules mediate leukocyte recruitment into the irradiated organs; modulation of this process may protect from radiation damage. Our objective was to characterize the requirement for intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in intestinal inflammatory response after abdominal irradiation. METHODS AND MATERIALS Endothelial ICAM-1 and VCAM-1 expression was determined using radiolabeled antibodies in mice 24 h and 14 days after irradiation with 10 Gy, or sham radiation. Leukocyte-endothelial cell interactions in intestinal venules were assessed using intravital microscopy, and the function of ICAM-1 and VCAM-1 in this process by using blocking antibodies and ICAM-1(-/-) mice. RESULTS The number of adherent leukocytes significantly increased 24 h after irradiation and remained elevated at 14 days. Treatment with anti-ICAM-1 antibodies and ICAM-1 genetic deficiency significantly reduced leukocyte adhesion 24 h after irradiation. At 14 days after irradiation, both wild-type and ICAM-1(-/-) mice had an upregulation of VCAM-1, expression, and VCAM-1 immunoneutralization, but not ICAM-1 immunoneutralization, significantly reduced leukocyte adhesion. In ICAM-1(-/-) mice, regeneration of the intestinal epithelium was enhanced relative to wild-type mice. CONCLUSIONS ICAM-1 plays a key role in leukocyte recruitment at early time points after abdominal irradiation, whereas VCAM-1 is the main molecular determinant of leukocyte recruitment at late time points.
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Affiliation(s)
- Meritxell Mollà
- Department of Gastroenterology, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
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15
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Vermaelen KY, Cataldo D, Tournoy K, Maes T, Dhulst A, Louis R, Foidart JM, Noël A, Pauwels R. Matrix metalloproteinase-9-mediated dendritic cell recruitment into the airways is a critical step in a mouse model of asthma. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2003; 171:1016-22. [PMID: 12847275 DOI: 10.4049/jimmunol.171.2.1016] [Citation(s) in RCA: 118] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Dendritic cells (DCs) appear to be strategically implicated in allergic diseases, including asthma. Matrix metalloproteinase (MMP)-9 mediates transmigration of inflammatory leukocytes across basement membranes. This study investigated the role of MMP-9 in airway DC trafficking during allergen-induced airway inflammation. MMP-9 gene deletion affected the trafficking of pulmonary DCs in a specific way: only the inflammatory transmigration of DCs into the airway lumen was impaired, whereas DC-mediated transport of airway Ag to the thoracic lymph nodes remained unaffected. In parallel, the local production of the Th2-attracting chemokine CC chemokine ligand 17/thymus and activation-regulated chemokine, which was highly concentrated in purified lung DCs, fell short in the airways of allergen-exposed MMP-9(-/-) mice. This was accompanied by markedly reduced peribronchial eosinophilic infiltrates and impaired allergen-specific IgE production. We conclude that the specific absence of MMP-9 activity inhibits the development of allergic airway inflammation by impairing the recruitment of DCs into the airways and the local production of DC-derived proallergic chemokines.
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Affiliation(s)
- Karim Y Vermaelen
- Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium.
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16
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Abstract
Dendritic cells (DCs) and epithelial cells are the first cells to encounter inhaled allergens. The response of these cell types to allergens is fundamentally different in asthmatics compared with nonasthmatics. DCs and epithelial cells interact through cell-cell interactions and through release of soluble mediators. The response of epithelial cells to allergens can profoundly modify the behavior of intramucosal DCs. Upon migration to the draining nodes, mucosal DCs undergo functional maturation and induce proliferation in naive T cells and primed Th2 cells. The implications of the DC-epithelial interaction for the pathogenesis of asthma is becoming increasingly clear by the use of mouse models and culture systems of human cells.
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Affiliation(s)
- Bart N Lambrecht
- Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
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17
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Fiorini M, Vermi W, Facchetti F, Moratto D, Alessandri G, Notarangelo L, Caruso A, Grigolato P, Ugazio AG, Notarangelo LD, Badolato R. Defective migration of monocyte‐derived dendritic cells in LAD‐1 immunodeficiency. J Leukoc Biol 2002. [DOI: 10.1189/jlb.72.4.650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Maurilia Fiorini
- Istituto di Medicina Molecolare “Angelo Nocivelli”, Università di Brescia, Italy
- Clinica Pediatrica, Università di Brescia, Italy
| | - William Vermi
- Cattedra di Anatomia Patologica, Università di Brescia, Italy and
| | - Fabio Facchetti
- Cattedra di Anatomia Patologica, Università di Brescia, Italy and
| | - Daniele Moratto
- Istituto di Medicina Molecolare “Angelo Nocivelli”, Università di Brescia, Italy
- Clinica Pediatrica, Università di Brescia, Italy
| | | | - Lucia Notarangelo
- Istituto di Medicina Molecolare “Angelo Nocivelli”, Università di Brescia, Italy
- Clinica Pediatrica, Università di Brescia, Italy
| | | | | | - Alberto G. Ugazio
- Istituto di Medicina Molecolare “Angelo Nocivelli”, Università di Brescia, Italy
- Clinica Pediatrica, Università di Brescia, Italy
| | - Luigi D. Notarangelo
- Istituto di Medicina Molecolare “Angelo Nocivelli”, Università di Brescia, Italy
- Clinica Pediatrica, Università di Brescia, Italy
| | - Raffaele Badolato
- Istituto di Medicina Molecolare “Angelo Nocivelli”, Università di Brescia, Italy
- Clinica Pediatrica, Università di Brescia, Italy
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18
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Cavanagh LL, Von Andrian UH. Travellers in many guises: the origins and destinations of dendritic cells. Immunol Cell Biol 2002; 80:448-62. [PMID: 12225381 DOI: 10.1046/j.1440-1711.2002.01119.x] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The migratory behaviour of dendritic cells (DC) is tightly linked to their differentiation state. Precursor DC constitutively repopulate normal tissues from the bloodstream, and are recruited in elevated numbers to sites of inflammation. Whilst maturing in response to antigenic stimulation, DC acquire the capability to enter lymph nodes via afferent lymphatic vessels, thus facilitating their presentation of antigen to naïve T cells. Peripheral blood monocytes constitute a second DC precursor population, which during an inflammatory response are recruited to the affected site where some differentiate into functional DC. The availability of separate DC precursor populations is thought to be significant for the character, amplification and perpetuation of the resultant immune response. In addition, the balance between steady-state trafficking of incompletely activated DC bearing self-antigens from the periphery, and the migration of fully mature DC from inflammatory sites into lymph nodes might have profound effects upon tolerance induction and activation of T cells, respectively.
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Affiliation(s)
- Lois L Cavanagh
- Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
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19
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Gironella M, Mollà M, Salas A, Soriano A, Sans M, Closa D, Engel P, Salas A, Piqué JM, Panés J. The role of P‐selectin in experimental colitis as determined by antibody immunoblockade and genetically deficient mice. J Leukoc Biol 2002. [DOI: 10.1189/jlb.72.1.56] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Meritxell Gironella
- Department of Gastroenterology, Institut de Malalties Digestives, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain
| | - Meritxell Mollà
- Department of Gastroenterology, Institut de Malalties Digestives, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain
| | - Azucena Salas
- Department of Gastroenterology, Institut de Malalties Digestives, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain
| | - Antonio Soriano
- Department of Gastroenterology, Institut de Malalties Digestives, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain
| | - Miquel Sans
- Department of Gastroenterology, Institut de Malalties Digestives, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain
| | - Daniel Closa
- Department of Medical Bioanalysis, IIBB‐CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain; and
| | - Pablo Engel
- Liver Unit, Hospital Clínic, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain
| | - Antonio Salas
- Department of Pathology, Hospital Mutua of Terrassa, Barcelona, Spain
| | - Josep M. Piqué
- Department of Gastroenterology, Institut de Malalties Digestives, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain
| | - Julián Panés
- Department of Gastroenterology, Institut de Malalties Digestives, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain
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20
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Vu Q, McCarthy KM, McCormack JM, Schneeberger EE. Lung dendritic cells are primed by inhaled particulate antigens, and retain MHC class II/antigenic peptide complexes in hilar lymph nodes for a prolonged period of time. Immunology 2002; 105:488-98. [PMID: 11985669 PMCID: PMC1782683 DOI: 10.1046/j.1365-2567.2002.01382.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Intratracheal (IT) administration of heat-killed Listeria monocytogenes (HKL) results in an influx of macrophage and dendritic cell (DC) precursors into the lung interstitium. Low-density, FcR+, interstitial lung cells isolated from rats instilled 24 hr before with HKL or vehicle alone, were > 90% Mar1+. After culturing with granulocyte-macrophage colony-stimulating factor (GM-CSF) for 3 days, up to 24% of the loosely adherent cells were DC that stimulated allogeneic T-cell proliferation in an mixed lymphocyte reaction (MLR) assay. After only an overnight incubation with GM-CSF, however, the capacity of interstitial Mar1+ cells to stimulate HKL immune T-cell proliferation without exogenous antigen was low. By contrast, when DC were isolated as major histocompatibility complex (MHC) class II+ cells from rat lungs at 1, 3, 7 and 14 days after HKL instillation and cultured overnight with GM-CSF, their antigen presentation capacity without added exogenous antigen was robust, but declined over the 2-week period. Interestingly, hilar lymph node DC maintained their HKL antigen-presenting capacity for up to 2 weeks after instillation of HKL. Following IT administration of PKH-26 labelled HKL, fluorescent or immunolabelled organisms were detected in OX62+ DC in airway epithelium, lung interstitium and hilar lymph nodes in situ and in MHC class II+ DC isolated from these sites. We conclude that newly immigrated Mar1+ lung DC precursors, while efficient in endocytosing particulate antigens, are incapable of eliciting a significant proliferative response from HKL-sensitized T cells. By contrast, MHC class II+ DC isolated from lungs and incubated overnight with GM-CSF induce vigorous antigen-specific T-cell proliferation. Antigen-loaded lung DC in hilar lymph nodes maintain their antigen presentation capacity for up to 2 weeks.
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Affiliation(s)
- Quynh Vu
- Molecular Pathology Unit, Massachusetts General Hospital East, Charlestown, MA 02129, USA
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21
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Grabbe S, Varga G, Beissert S, Steinert M, Pendl G, Seeliger S, Bloch W, Peters T, Schwarz T, Sunderkötter C, Scharffetter-Kochanek K. β2 integrins are required for skin homing of primed T cells but not for priming naive T cells. J Clin Invest 2002. [DOI: 10.1172/jci0211703] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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22
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Grabbe S, Varga G, Beissert S, Steinert M, Pendl G, Seeliger S, Bloch W, Peters T, Schwarz T, Sunderkötter C, Scharffetter-Kochanek K. Beta2 integrins are required for skin homing of primed T cells but not for priming naive T cells. J Clin Invest 2002; 109:183-92. [PMID: 11805130 PMCID: PMC150832 DOI: 10.1172/jci11703] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Beta2 integrins are of critical importance for leukocyte extravasation through vascular endothelia and for T cell activation. To elucidate the role of beta2 integrins in T cell-mediated immune responses, allergic contact dermatitis (ACD), irritant dermatitis, and delayed-type hypersensitivity (DTH) were assessed in mice lacking the beta2 integrin subunit, CD18. ACD and DTH responses, but not edema formation, were severely suppressed in CD18(-/-) mice. Extravasation of CD18(-/-) T cells into eczematous skin lesions was greatly impaired, whereas migration of Langerhans cell precursors and dendritic cells was normal in CD18(-/-) mice. CD18(-/-)lymph nodes (LNs) contained an abnormal population of CD3(-)CD44(high) lymphocytes and showed evidence of widespread T cell activation. T cells from regional LNs of sensitized CD18(-/-) mice proliferated in response to hapten challenge, and subcutaneous injection of sensitized syngeneic LN cells directly into ears of hapten-challenged naive recipients restored the defective ACD in CD18(-/-) mice, suggesting that CD18 is not required for priming of naive T cells but is indispensable for T cell extravasation. Thus, a dysfunction of T cells, in addition to granulocytes, may contribute to the pathophysiology of leukocyte adhesion deficiency type I, which arises from mutations in the human CD18 gene.
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Affiliation(s)
- Stephan Grabbe
- Department of Dermatology, University of Münster, Münster, Germany.
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23
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Maus U, Huwe J, Ermert L, Ermert M, Seeger W, Lohmeyer J. Molecular pathways of monocyte emigration into the alveolar air space of intact mice. Am J Respir Crit Care Med 2002; 165:95-100. [PMID: 11779737 DOI: 10.1164/ajrccm.165.1.2106148] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The adhesive interactions involved in monocyte recruitment to the alveolar space in vivo are only poorly defined. To study these interactions, we used a recently developed mouse model that allowed the separation and quantification of freshly recruited monocytes, resident alveolar macrophages (rAM), neutrophils, and lymphocytes in the bronchoalveolar compartment by fluorescence activated cell sorting technology. In these mice, the combined intratracheal administration of the monocyte chemoattractant JE/monocyte chemotactic protein (MCP)-1 and low dose Escherichia coli lipopolysaccharide (LPS) induces a self-limiting pulmonary inflammatory response, characterized by well-controlled sequelae of both neutrophil and monocyte emigration into the alveolar space. In contrast, challenge with JE/MCP-1 provokes the emigration only of monocytes in the absence of lung inflammation. Using an array of function-blocking monoclonal antibodies (mAb) (anti-CD11a, -CD11b, -CD18, -CD49d, -CD54, and -CD106), we characterized the adhesive interactions underlying the transendothelial and transepithelial leukocyte traffic in intact animals. Alveolar monocyte recruitment elicited by JE/MCP-1 alone was strictly dependent on CD11b/CD18, CD54, and CD49d, and partly dependent on CD11a, but not dependent on CD106. In response to JE/MCP-1 plus E. coli LPS, we observed additional engagement of CD11a and CD106 for enhanced alveolar monocyte transmigration. Comigrating neutrophils were found to primarily utilize CD11b, CD18, and CD54, but not CD49d, CD106, or, surprisingly, CD11a. This contrasted with the effect of CD11a on alveolar challenge with macrophage inflammatory protein (MIP)-1alpha instead of JE/MCP-1. In conclusion, we found that in an intact mouse model allowing detailed phenotyping of leukocyte traffic into the alveolar space, the molecular pathways involved in JE/MCP-1-driven monocyte efflux differed under noninflammatory and inflammatory (presence of LPS) conditions. Moreover, the profile of adhesive interactions underlying the monocyte efflux differed from that characterizing neutrophil trafficking.
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Affiliation(s)
- Ulrich Maus
- Departments of Internal Medicine and Pathology, Justus-Liebig-University, Giessen, Germany.
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24
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Xu H, Guan H, Zu G, Bullard D, Hanson J, Slater M, Elmets CA. The role of ICAM-1 molecule in the migration of Langerhans cells in the skin and regional lymph node. Eur J Immunol 2001; 31:3085-93. [PMID: 11592085 PMCID: PMC4894309 DOI: 10.1002/1521-4141(2001010)31:10<3085::aid-immu3085>3.0.co;2-b] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
ICAM-1 (CD54) plays an important role in the cell-cell interaction and migration of leukocytes. Previous studies have shown that ICAM-1 is involved in inflammatory reactions and that a defect in ICAM-1 gene inhibits allergic contact hypersensitivity. This study indicates that the migration of hapten presenting Langerhans cells into the regional lymph nodes was significantly reduced in ICAM-1-deficient mice compared to wild-type C57BL/6 mice. The reduced number of dendritic cells in regional lymph nodes did not result from abnormal migration of Langerhans cells into the skin of ICAM-1-deficient mice. The concentration and distribution of Langerhans cells in the naïve skin of ICAM-1-deficient mice was equal to that of wild-type mice. Following hapten sensitization, Langerhans cell migration out of the skin and recruitment of fresh Langerhans cells back to the epidermis was not affected in ICAM-1-deficient mice. Further experiments demonstrated that ICAM-1 deficiency on lymphatic endothelium rather than on dendritic cells was responsible for the reduced migration of Langerhans cells into draining lymph nodes. This study indicates that ICAM-1 regulates the migration of dendritic cells into regional lymph nodes but not into or out of the skin.
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Affiliation(s)
- H Xu
- Department of Dermatology, University of Alabama at Birmingham, Birmingham 35294, USA.
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25
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Bouvard D, Brakebusch C, Gustafsson E, Aszódi A, Bengtsson T, Berna A, Fässler R. Functional consequences of integrin gene mutations in mice. Circ Res 2001; 89:211-23. [PMID: 11485971 DOI: 10.1161/hh1501.094874] [Citation(s) in RCA: 152] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Integrins are cell-surface receptors responsible for cell attachment to extracellular matrices and to other cells. The application of mouse genetics has significantly increased our understanding of integrin function in vivo. In this review, we summarize the phenotypes of mice carrying mutant integrin genes and compare them with phenotypes of mice lacking the integrin ligands.
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Affiliation(s)
- D Bouvard
- Department of Experimental Pathology, Lund University, Lund, Sweden.
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26
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Sans M, Salas A, Soriano A, Prats N, Gironella M, Pizcueta P, Elena M, Anderson DC, Piqué JM, Panés J. Differential role of selectins in experimental colitis. Gastroenterology 2001; 120:1162-72. [PMID: 11266380 DOI: 10.1053/gast.2001.23252] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS The role of selectins in experimental colitis remains unknown. The aims of this study were to characterize the time-course expression of selectins in trinitrobenzene sulfonic acid (TNBS)-induced colitis, the functional role of selectins in colonic leukocyte-endothelial cell interactions, and the therapeutic usefulness of selectin blockade in this model. METHODS Control and TNBS-induced colitic rats were studied. Expression of P- and E-selectin was assessed by the radiolabeled antibody technique, and L-selectin by flow cytometry. Leukocyte-endothelial cell interactions were studied in colonic venules by using intravital microscopy under basal conditions and after P-, E-, or L-selectin immunoblockade. Additional groups of animals were treated with anti-P-selectin antibody, a nonbinding antibody, or dexamethasone, for 7 days. RESULTS P-selectin and E-selectin expression were markedly up-regulated in colitic rats. Increased leukocyte rolling was abrogated by anti-P-selectin, but only attenuated by anti-E- or anti-L-selectin antibodies. Only pretreatment with anti-P- selectin decreased leukocyte adhesion. Animals chronically treated with dexamethasone, but not with anti- P-selectin, had significantly lower macroscopic and histologic damage scores, colon weight, and myeloperoxidase (MPO) activity than those treated with nonbinding antibody. CONCLUSIONS P-selectin plays a key role on leukocyte rolling and its blockade attenuates leukocyte adhesion in TNBS-induced colitis. However, treatment with an anti-P-selectin antibody does not significantly improve colitis.
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Affiliation(s)
- M Sans
- Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Catalonia, Spain
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Caux C, Ait-Yahia S, Chemin K, de Bouteiller O, Dieu-Nosjean MC, Homey B, Massacrier C, Vanbervliet B, Zlotnik A, Vicari A. Dendritic cell biology and regulation of dendritic cell trafficking by chemokines. SPRINGER SEMINARS IN IMMUNOPATHOLOGY 2000; 22:345-69. [PMID: 11155441 DOI: 10.1007/s002810000053] [Citation(s) in RCA: 217] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
DC (dendritic cells) represent an heterogeneous family of cells which function as sentinels of the immune system. They traffic from the blood to the tissues where, while immature, they capture antigens. Then, following inflammatory stimuli, they leave the tissues and move to the draining lymphoid organs where, converted into mature DC, they prime naive T cells. The key role of DC migration in their sentinel function led to the investigation of the chemokine responsiveness of DC populations during their development and maturation. These studies have shown that immature DC respond to many CC and CXC chemokines (MIP-1 alpha, MIP-1 beta, MIP-3 alpha, MIP-5, MCP-3, MCP-4, RANTES, TECK and SDF-1) which are inducible upon inflammatory stimuli. Importantly, each immature DC population displays a unique spectrum of chemokine responsiveness. For examples, Langerhans cells migrate selectively to MIP-3 alpha (via CCR6), blood CD11c+ DC to MCP chemokines (via CCR2), monocytes derived-DC respond to MIP-1 alpha/beta (via CCR1 and CCR5), while blood CD11c- DC precursors do not respond to any of these chemokines. All these chemokines are inducible upon inflammatory stimuli, in particular MIP-3 alpha, which is only detected within inflamed epithelium, a site of antigen entry known to be infiltrated by immature DC. In contrast to immature DC, mature DC lose their responsiveness to most of these inflammatory chemokines through receptor down-regulation or desensitization, but acquire responsiveness to ELC/MIP-3 beta and SLC/6Ckine as a consequence of CCR7 up-regulation. ELC/MIP-3 beta and SLC/6Ckine are specifically expressed in the T-cell-rich areas where mature DC home to become interdigitating DC. Altogether, these observations suggest that the inflammatory chemokines secreted at the site of pathogen invasion will determine the DC subset recruited and will influence the class of the immune response initiated. In contrast, MIP-3 beta/6Ckine have a determinant role in the accumulation of antigenloaded mature DC in T cell-rich areas of the draining lymph node, as illustrated by recent observations in mice deficient for CCR7 or SLC/6Ckine. A better understanding of the regulation of DC trafficking might offer new opportunities of therapeutic interventions to suppress, stimulate or deviate the immune response.
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Affiliation(s)
- C Caux
- Schering-Plough Laboratory for Immunological Research, 27 chemin des Peupliers, BP 11, 69571 Dardilly, France
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