Leucocyte expression of the chemokine scavenger D6

2006 ◽  
Vol 34 (6) ◽  
pp. 1002-1004 ◽  
Author(s):  
C.S. McKimmie ◽  
G.J. Graham
Keyword(s):  
Lymph Node ◽  
Chemokine Receptor ◽  
Inflammatory Responses ◽  
Lymphatic Endothelium ◽  
Cutaneous Inflammation ◽  
Leucocyte Migration ◽  
Successful Resolution ◽  
Inflammatory Chemokines

Selective sequestration of inflammatory chemokines is critical for the successful resolution of inflammatory responses in vivo. D6 is an atypical chemokine receptor that scavenges inflammatory chemokines and is pivotal in resolving models of chemokine-driven cutaneous inflammation. We provide evidence that expression of D6 is not limited to the lymphatic endothelium at sites of inflammation as previously believed. Instead we postulate that D6 expression in leucocytes may have a significant impact upon chemokine bioavailability during the resolution phase of inflammation. D6 expressed on the lymphatic endothelia may instead have complementary roles in preventing inappropriate leucocyte migration to the lymph node by keeping the endothelium free from inflammatory chemokines.

scholarly journals Analysis of combinatorial chemokine receptor expression dynamics using multi-receptor reporter mice

2021 ◽  
Author(s):  
Laura Medina-Ruiz ◽  
Robin Bartolini ◽  
Douglas P Dyer ◽  
Francesca Vidler ◽  
Catherine Hughes ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Inflammatory Responses ◽  
Expression Patterns ◽  
Myeloid Cell ◽  
Receptor Expression ◽  
In Vivo Models ◽  
Chemokine Receptor Expression ◽  
Reporter Mice ◽  
Inflammatory Chemokines

Inflammatory chemokines and their receptors are central to the development of inflammatory/immune pathologies. The apparent complexity of this system, coupled with lack of appropriate in vivo models, has limited our understanding of how chemokines orchestrate inflammatory responses and has hampered attempts at targeting this system in inflammatory disease. Novel approaches are therefore needed to provide crucial biological, and therapeutic, insights into the chemokine-chemokine receptor family. Here, we report the generation of transgenic multi-chemokine receptor reporter mice in which spectrally-distinct fluorescent reporters mark expression of CCRs 1, 2, 3 and 5, key receptors for myeloid cell recruitment in inflammation. Analysis of these animals has allowed us to define, for the first time, individual and combinatorial receptor expression patterns on myeloid cells in resting and inflamed conditions. Our results demonstrate that chemokine receptor expression is highly specific, and more selective than previously anticipated.

Chemokine sequestration by atypical chemokine receptors

2006 ◽  
Vol 34 (6) ◽  
pp. 1009-1013 ◽  
Author(s):  
C.A.H. Hansell ◽  
C.V. Simpson ◽  
R.J.B. Nibbs
Keyword(s):  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Trafficking ◽  
Leucocyte Migration ◽  
Acquired Immune Responses ◽  
G Protein Coupled ◽  
Receptor Family

Leucocyte migration is essential for robust immune and inflammatory responses, and plays a critical role in many human diseases. Chemokines, a family of small secreted protein chemoattractants, are of fundamental importance in this process, directing leucocyte trafficking by signalling through heptahelical G-protein-coupled receptors expressed by the migrating cells. However, several mammalian chemokine receptors, including D6 and CCX-CKR (ChemoCentryx chemokine receptor), do not fit existing models of chemokine receptor function, and do not even appear to signal in response to chemokine binding. Instead, these ‘atypical’ chemokine receptors are biochemically specialized for chemokine sequestration, acting to regulate chemokine bioavailability and thereby influence responses through signalling-competent chemokine receptors. This is of critical importance in vivo, as mice lacking D6 show exaggerated cutaneous inflammatory responses and an increased susceptibility to the development of skin cancer. CCX-CKR, on the other hand, is predicted to modulate homoeostatic lymphocyte and dendritic cell trafficking, key migratory events in acquired immune responses that are directed by CCX-CKR-binding chemokines. Thus studies on ‘atypical’ chemokine receptors are revealing functional and biochemical diversity within the chemokine receptor family and providing insights into novel mechanisms of chemokine regulation.

scholarly journals TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events

2008 ◽  
Vol 205 (11) ◽  
pp. 2609-2621 ◽  
Author(s):  
Karen A. Cavassani ◽  
Makoto Ishii ◽  
Haitao Wen ◽  
Matthew A. Schaller ◽  
Pamela M. Lincoln ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Tissue Injury ◽  
Cytokine Levels ◽  
Inflammatory Chemokines ◽  
Inflammatory Processes ◽  
Factor Α ◽  
Injury Models ◽  
Dying Cells ◽  
Necrosis Factor

Ligands from dying cells are a source of Toll-like receptor (TLR) activating agents. Although TLR3 is known to respond to RNA from necrotic cells, the relative importance of this response in vivo during acute inflammatory processes has not been fully explored. We observed the involvement of TLR3 activation during experimental polymicrobial septic peritonitis and ischemic gut injury in the absence of an exogenous viral stimulus. In TLR3-deficient mice, increased chemokine/cytokine levels and neutrophil recruitment characterized the initial inflammatory responses in both injury models. However, the levels of inflammatory chemokines and tumor necrosis factor α quickly returned to baseline in tlr3−/− mice, and these mice were protected from the lethal effects of sustained inflammation. Macrophages from tlr3−/− mice responded normally to other TLR ligands but did not respond to RNA from necrotic neutrophils. Importantly, an immunoneutralizing antibody directed against TLR3 attenuated the generation of inflammatory chemokines evoked by byproducts from necrotic neutrophils cultured with wild-type macrophages. In vivo, anti-TLR3 antibody attenuated the tissue injury associated with gut ischemia and significantly decreased sepsis-induced mortality. Collectively, these data show that TLR3 is a regulator of the amplification of immune response and serves an endogenous sensor of necrosis, independent of viral activation.

scholarly journals CC Chemokine Receptor (CCR)4 and the CCR10 Ligand Cutaneous T Cell–attracting Chemokine (CTACK) in Lymphocyte Trafficking to Inflamed Skin

2001 ◽  
Vol 194 (10) ◽  
pp. 1541-1547 ◽  
Author(s):  
Yvonne Reiss ◽  
Amanda E. Proudfoot ◽  
Christine A. Power ◽  
James J. Campbell ◽  
Eugene C. Butcher
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Chemokine Receptor ◽  
Memory T Cells ◽  
Delayed Type Hypersensitivity ◽  
Wild Type ◽  
Cc Chemokine ◽  
Skin Homing

The chemokine thymus and activation-regulated chemokine (TARC; CCL17) is displayed by cutaneous (but not intestinal) venules, and is thought to trigger vascular arrest of circulating skin homing memory T cells, which uniformly express the TARC receptor CC chemokine receptor (CCR)4. Cutaneous T cell–attracting chemokine (CTACK; CCL27), expressed by skin keratinocytes, also attracts cutaneous memory T cells, and is hypothesized to assist in lymphocyte recruitment to skin as well. Here we show that chronic cutaneous inflammation induces CD4 T cells expressing E-selectin binding activity (a marker of skin homing memory cells) in draining lymph node, and that these E-selectin ligand+ T cells migrate efficiently to TARC and to CTACK. In 24 h in vivo homing assays, stimulated lymph node T cells from wild-type mice or, surprisingly, from CCR4-deficient donors migrate efficiently to inflamed skin; and an inhibitory anti-CTACK antibody has no effect on wild-type lymphocyte recruitment. However, inhibition with anti-CTACK monoclonal antibody abrogates skin recruitment of CCR4-deficient T cells. We conclude that CTACK and CCR4 can both support homing of T cells to skin, and that either one or the other is required for lymphocyte recruitment in cutaneous delayed type hypersensitivity.

scholarly journals Hypoxic-Inflammatory Responses under Acute Hypoxia: In Vitro Experiments and Prospective Observational Expedition Trial

2020 ◽  
Vol 21 (3) ◽  
pp. 1034 ◽  
Author(s):  
Tobias Kammerer ◽  
Valentina Faihs ◽  
Nikolai Hulde ◽  
Manfred Stangl ◽  
Florian Brettner ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Chemokine Receptor ◽  
Hypobaric Hypoxia ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Acute Mountain Sickness ◽  
Receptor Type ◽  
Adaptation To Hypoxia

Induction of hypoxia-inducible-factor-1α (HIF-1α) pathway and HIF-target genes allow adaptation to hypoxia and are associated with reduced incidence of acute mountain sickness (AMS). Little is known about HIF-pathways in conjunction with inflammation or exercise stimuli under acute hypobaric hypoxia in non-acclimatized individuals. We therefore tested the hypotheses that (1) both hypoxic and inflammatory stimuli induce hypoxic-inflammatory signaling pathways in vitro, (2) similar results are seen in vivo under hypobaric hypoxia, and (3) induction of HIF-dependent genes is associated with AMS in 11 volunteers. In vitro, peripheral blood mononuclear cells (PBMCs) were incubated under hypoxic (10%/5% O2) or inflammatory (CD3/CD28) conditions. In vivo, Interleukin 1β (IL-1β), C-X-C Chemokine receptor type 4 (CXCR-4), and C-C Chemokine receptor type 2 (CCR-2) mRNA expression, cytokines and receptors were analyzed under normoxia (520 m above sea level (a.s.l.)), hypobaric hypoxia (3883 m a.s.l.) before/after exercise, and after 24 h under hypobaric hypoxia. In vitro, isolated hypoxic (p = 0.004) or inflammatory (p = 0.006) stimuli induced IL-1β mRNA expression. CCR-2 mRNA expression increased under hypoxia (p = 0.005); CXCR-4 mRNA expression remained unchanged. In vivo, cytokines, receptors, and IL-1β, CCR-2 and CXCR-4 mRNA expression increased under hypobaric hypoxia after 24 h (all p ≤ 0.05). Of note, proinflammatory IL-1β and CXCR-4 mRNA expression changes were associated with symptoms of AMS. Thus, hypoxic-inflammatory pathways are differentially regulated, as combined hypoxic and exercise stimulus was stronger in vivo than isolated hypoxic or inflammatory stimulation in vitro.

A TLR2 ligand suppresses inflammation by modulation of chemokine receptors and redirection of leukocyte migration

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4224-4231 ◽  
Author(s):  
Clive S. McKimmie ◽  
Mark Moore ◽  
Alasdair R. Fraser ◽  
Thomas Jamieson ◽  
Damo Xu ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Receptor Expression ◽  
Adaptive Responses ◽  
Chemokine Receptor Expression ◽  
Tlr2 Ligand ◽  
And Migration

Abstract Toll-like receptors orchestrate rapid local protective innate-immune responses to invading pathogens and optimize leukocyte priming of subsequent adaptive responses. Paradoxically, systemic excess of the TLR2 ligand, bacterial lipoprotein (BLP), suppresses peripheral inflammatory responses. Here, we demonstrate that this phenomenon is regulated via the TLR2-dependent, cell-autonomous down-regulation of inflammatory chemokine receptor expression on a variety of leukocyte subsets. Remarkably, BLP mediated no effect on constitutive chemokine receptor expression. By tracking adoptively transferred wild-type and TLR2−/− leukocytes in vivo, we observed that BLP mediated chemokine receptor switching directed leukocytes away from inflamed sites toward secondary lymphoid organs. These data highlight a novel role for TLR ligands, such as BLP, in regulating leukocyte retention and migration away from innate immune lesions via discrete constitutive and inflammatory chemokine receptor regulation.

scholarly journals Anti-CD43 Inhibition of  T Cell Homing

1997 ◽  
Vol 185 (8) ◽  
pp. 1493-1498 ◽  
Author(s):  
Leslie M. McEvoy ◽  
Hailing Sun ◽  
John G. Frelinger ◽  
Eugene C. Butcher
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
Inflammatory Responses ◽  
Lymphocyte Activation ◽  
Cell Interaction ◽  
Lymphoid Tissues ◽  
High Endothelial Venules ◽  
Novel Target

The homing of lymphocytes from the blood is controlled by specialized processes of lymphocyte–endothelial cell interaction. Interference with these processes offers the potential to manipulate lymphocyte traffic, and thus to modulate normal and pathologic immune and inflammatory responses. We selected antilymphocyte monoclonal antibodies (mAbs) for inhibition of lymphocyte binding in vitro to lymph node high endothelial venules (HEV), specialized vessels that support lymphocyte recruitment into lymph nodes. mAb L11 blocks T cell binding to lymph node and Peyer's patch HEV and inhibits T cell extravasation from the blood into organized secondary lymphoid tissues. In contrast, L11 has no effect on lymphocyte binding to purified vascular ligands for L-selectin, α4β7, or LFA-1, suggesting that it inhibits by a novel mechanism. The L11 antigen is CD43, a sialomucin implicated in vitro in regulation of lymphocyte activation, whose expression is often dysregulated in the Wiskott-Aldrich syndrome. CD43 represents a novel target for experimental and therapeutic manipulation of lymphocyte traffic and may help regulate T cell distribution in vivo.

Anti-β2 Glycoprotein I Antibodies Cause Inflammation and Recruit Dendritic Cells in Platelet Clearance

2001 ◽  
Vol 86 (11) ◽  
pp. 1257-1263 ◽  
Author(s):  
Attilio Bondanza ◽  
Angelo Manfredi ◽  
Valérie Zimmermann ◽  
Matteo Iannacone ◽  
Angela Tincani ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Inflammatory Responses ◽  
Glycoprotein I ◽  
Activated Platelets ◽  
Tnf Α ◽  
Per Se ◽  
Antigen Presenting ◽  
Antiinflammatory Cytokine

SummaryScavenger phagocytes are mostly responsible for the in vivo clearance of activated or senescent platelets. In contrast to other particulate substrates, the phagocytosis of platelets does not incite pro-inflammatory responses in vivo. This study assessed the contribution of macrophages and dendritic cells (DCs) to the clearance of activated platelets. Furthermore, we verified whether antibodies against the β2 Glycoprotein I (β2GPI), which bind to activated platelets, influence the phenomenon. DCs did not per se internalise activated platelets. In contrast, macrophages efficiently phagocytosed platelets. In agreement with the uneventful nature of the clearance of platelets in vivo, phagocytosing macrophages did not release IL-1β, TNF-α or IL-10. β2GPI bound to activated platelets and was required for their recognition by anti-ββ2GPI antibodies. DCs internalised platelets opsonised by anti-ββ2GPI antibodies. The phagocytosis of opsonised platelets determined the release of TNF-α and IL-1β by DCs and macrophages. Phagocytosing macrophages, but not DCs, secreted the antiinflammatory cytokine IL-1β0. We conclude that anti-ββ2GPI antibodies cause inflammation during platelet clearance and shuttle platelet antigens to antigen presenting DCs.

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