CD45 modulation of CXCR1 and CXCR2 in human polymorphonuclear leukocytes

Mitchell, Gordon; Khandaker, Masud H.; Rahimpour, R.; Xu, Luoling; Lazarovits, Andrew I.; Pickering, J. Geoffrey; Suria, Hamza; Madrenas, Joaquı́n; Pomerantz, David K.; Feldman, Ross D.; Kelvin, David J.

doi:10.1002/(sici)1521-4141(199905)29:05<1467::aid-immu1467>3.0.co;2-5

Cited by 21 publications

(10 citation statements)

References 32 publications

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“…Alternatively, the reduced expression of CXCR1 and CXCR2 could be explained by the presence of TNF‐ α , which leads to a proteolytic degradation of IL‐8 receptors [35]. Apart from soluble cell mediators, triggering of CD45 tyrosine phosphatase activity has been shown to down‐regulate IL‐8 receptors on neutrophils via tyrosine kinase activation in vitro [36]. Different sentivivity of chemokine receptors to regulatory intracellular signalling pathways or proteolytic clipping could contribute to the differential expression of receptors on activated leucocytes at the site of inflamation.…”

Section: Discussionmentioning

confidence: 99%

Surface expression of CC- and CXC-chemokine receptors on leucocyte subsets in inflammatory joint diseases

Brühl

Wagner

Kellner

et al. 2001

Clinical and Experimental Immunology

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SUMMARYChemokine receptors play a crucial role in the recruitment of leucocyte subsets into inflamed tissue. Using FACS analysis we have studied the surface expression of different CC-and CXC-chemokine receptors on synovial fluid (SF) and peripheral blood leucocytes from 20 patients with various forms of arthritis. In the SF the majority T cells stained positive for CCR5 (93%) and CCR2 (57%), compared to the peripheral blood (36% and 25%). In addition, most of the T cells expressed CXCR4 in both compartments, with a somewhat higher percentage in the SF (90%) versus peripheral blood (83%). To date little information is available on chemokine receptor expression on monocytes in arthritis. We report a marked increase of CCR5 1 monocytes in the SF (87%) compared to the peripheral blood (22%). In contrast, the frequency of CXCR1 1 , CXCR2 1 , CXCR4 1 and CCR1 1 monocytes was considerably lower in the SF than in the peripheral blood. Moreover, we report the expression CXCR4 on neutrophils in the SF. Approximately 60% of neutrophils stained positive for CXCR4 in the SF, while in the peripheral blood the number of CXCR4 1 neutrophils was low (24%). Surface expression of CXCR1 and CXCR2 was significantly reduced on SF neutrophils (53% and 68%) compared to the peripheral blood. Chemokine receptors are differentially expressed on leucocyte subsets in arthritis. The identification of their pattern of expression might help to identify suitable targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Surface expression of CC- and CXC-chemokine receptors on leucocyte subsets in inflammatory joint diseases

Brühl

Wagner

Kellner

et al. 2001

Clinical and Experimental Immunology

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“…31 Pretreatment of neutrophils with the anti-CD45 mAb Bra11 reduces cells surface expression of CXCR1 and CXCR2. 32 This effect is completely tyrphostin reversible. 32 We used Bra55, another anti-CD45 mAb that deactivates neutrophil chemotaxis without affecting receptor density, 32 and found that the inhibition of AT III-induced directed migration by Bra55 was reversed by tyrphostin.…”

Section: The Receptormentioning

confidence: 94%

“…32 This effect is completely tyrphostin reversible. 32 We used Bra55, another anti-CD45 mAb that deactivates neutrophil chemotaxis without affecting receptor density, 32 and found that the inhibition of AT III-induced directed migration by Bra55 was reversed by tyrphostin. Furthermore, the addition of tyrphostin abrogated AT III-induced deactivation of IL-8-triggered chemotaxis and thereby restored the migration of neutrophils to IL-8.…”

Section: The Receptormentioning

confidence: 94%

Cell-surface heparan sulfate proteoglycan–mediated regulation of human neutrophil migration by the serpin antithrombin III

Dunzendorfer

Kaneider

Rabensteiner

et al. 2001

Blood

105

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The serpin antithrombin III (AT III) is reported to have hemostasis-regulating and anti-inflammatory properties. To determine its ability to influence thrombin-independent leukocyte responses, the direct effects of the AT III concentrate Kybernin P and a monoclonal antibody-purified AT III on neutrophil migration were studied. Chemotactic activity of human neutrophils isolated from the blood of healthy donors was determined in modified Boyden microchemotaxis chambers, and binding studies were performed according to standard experimental protocols. Preincubation in vitro of neutrophils with Kybernin P or immune-adsorbed AT III significantly deactivated migration toward fMet-Leu-Phe, or interleukin-8 (IL-8), in a concentration-dependent manner. In the absence of additional attractants, neutrophils exhibited a migratory response toward gradients of AT III preparations. True chemotaxis was confirmed in checkerboard assays. Analyses revealed that the AT III heparin-binding site interacts with neutrophil membrane-associated heparan sulfate proteoglycan receptors. Mechanisms of intracellular signaling differed; the deactivation of IL-8-induced chemotaxis resulted from tyrphostin-sensitive interactions of AT III-signaling with the IL-8 signal transduction pathway, whereas AT III-induced chemotaxis involved protein kinase C and phosphodiesterases. Signaling similarities between AT III and the proteoglycan syndecan-4 may suggest the binding of AT III to this novel type of membrane receptor. Under physiological conditions, AT III may prevent neutrophils from premature activation. Moreover, the systemic administration of AT III concentrate could have beneficial effects in combating systemic inflammation.

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“…At the cellular level, the CD45 phosphatase targets several families of proteins, including the Src family tyrosine kinases and Janus kinases (41), resulting in positive or negative signaling (2, 4, 54). In addition to lymphocytes, recent studies demonstrate that CD45 can modulate activation and proliferation of several inflammatory cell types including granulocytes, mast cells and monocyte-lineage cells, broadening its role as a regulator of inflammatory responses (8, 20, 35, 48, 57). …”

Section: Introductionmentioning

confidence: 99%

CD45 Isoform Expression in Microglia and Inflammatory Cells in HIV‐1 Encephalitis

et al. 2006

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CD45 is a membrane tyrosine phosphatase that modulates the function of the hematopoietic cells. In vitro, agonist antibodies to CD45RO or CD45RB isoforms have been shown to suppress microglial activation, but whether microglia in vivo express these isoforms in HIV encephalitis (HIVE) is unknown. Brain sections from control and HIVE were immunostained for CD45 isoforms using exon-specific antibodies (RA, RB, RC and RO). RA and RC were limited to rare lymphocytes, while RB expression was robust in microglia and inflammatory cells. RO was low in control microglia, but increased in HIVE. RO was also localized to macrophages and CD8+ T cells. Targeting CD45 in vivo with isoform-specific antibodies remains a therapeutic option for neuroinflammatory diseases. Pathol 2006;16:256-265. Brain INTRODUCTIONThe leukocyte common antigen (LCA: CD45) is a prototype transmembrane protein tyrosine phosphatase (PTPase) and is expressed in all nucleated hematopoietic cells (54). The CD45 protein exists as multiple isoforms as a result of alternative splicing of variable exons (4/A, 5/B and 6/C); the largest isoform (ABC) includes all three of these exons and the smallest isoform (O) lacks all three exons. Five different isoforms of CD45 (ABC, AB, BC, B and O) have been identified on human leukocytes and these can be recognized by antibodies specific to variable exons (A, B or C) or by αCD45RO (45). Although the extracellular domains differ among different isoforms, all forms share identical transmembrane and cytoplasmic domains including the phosphatase domains (52, 54).CD45 is one of the most abundantly expressed molecules in lymphocytes (comprising approximately 10% of all surface proteins) and is crucial in lymphocyte development and antigen signaling (2,12,23,54). Consequently, CD45 mutations are associated with severe combined immunodeficiency in mice and humans (5,28,51). In lymphocytes, CD45 is expressed in a cell subset-specific and activation-dependent manner. For instance, naïve T cells express a high molecular weight isoform (RA+/RO−) but upon activation switch to the smallest isoform (RA−/RO+) (16,31). At the cellular level, the CD45 phosphatase targets several families of proteins, including the Src family tyrosine kinases and Janus kinases (41), resulting in positive or negative signaling (2,4,54). In addition to lymphocytes, recent studies demonstrate that CD45 can modulate activation and proliferation of several inflammatory cell types including granulocytes, mast cells and monocytelineage cells, broadening its role as a regulator of inflammatory responses (8,20,35,48,57).In the central nervous system (CNS), microglia constitute a distinct glial cell population that is derived from hematopoietic cells in the bone marrow (17, 29, 42). As resident brain macrophages, microglia function as sentries, but when activated they can mediate tissue damage, a scenario considered for several CNS inflammatory disorders (10,15,27). In AIDS dementia and HIV encephalitis (HIVE), microglia and macrophages are productively infected by ...

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CD45 modulation of CXCR1 and CXCR2 in human polymorphonuclear leukocytes

Cited by 21 publications

References 32 publications

Surface expression of CC- and CXC-chemokine receptors on leucocyte subsets in inflammatory joint diseases

Surface expression of CC- and CXC-chemokine receptors on leucocyte subsets in inflammatory joint diseases

Cell-surface heparan sulfate proteoglycan–mediated regulation of human neutrophil migration by the serpin antithrombin III

CD45 Isoform Expression in Microglia and Inflammatory Cells in HIV‐1 Encephalitis

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