CXC chemokine ligand 4 (CXCL4) down-regulates CC chemokine receptor expression on human monocytes

During acute inflammation, monocytes are essential in abolishing invading micro-organisms and encouraging wound healing. Recruitment by CC chemokines is an important step in targeting monocytes to the inflamed tissue. However, cell surface expression of the corresponding chemokine receptors is subject to regulation by various endogenous stimuli which so far have not been comprehensively identified. We report that the platelet-derived CXC chemokine ligand 4 (CXCL4), a known activator of human monocytes, induces down-regulation of CC chemokine receptors (CCR) 1, −2, and −5, resulting in drastic impairment of monocyte chemotactic migration towards cognate CC chemokine ligands (CCL) for these receptors. Interestingly, CXCL4-mediated down-regulation of CCR1, CCR2 and CCR5 was strongly dependent on the chemokine’s ability to stimulate autocrine/paracrine release of TNF-α. In turn, TNF-α induced the secretion CCL3 and CCL4, two chemokines selective for CCR1 and CCR5, while the secretion of CCR2-ligand CCL2 was TNF-α-independent. Culture supernatants of CXCL4-stimulated monocytes as well as chemokine-enriched preparations thereof reproduced CXCL4-induced CCR down-regulation. In conclusion, CXCL4 may act as a selective regulator of monocyte migration by stimulating the release of autocrine, receptor-desensitizing chemokine ligands. Our results stress a co-ordinating role for CXCL4 in the cross-talk between platelets and monocytes during early inflammation.

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Neuropeptide substance P upregulates chemokine and chemokine receptor expression in primary mouse neutrophils

AJP Cell Physiology ◽

10.1152/ajpcell.00060.2007 ◽

2007 ◽

Vol 293 (2) ◽

pp. C696-C704 ◽

Cited By ~ 43

Author(s):

Jia Sun ◽

Raina Devi Ramnath ◽

Madhav Bhatia

Keyword(s):

Substance P ◽

Chemokine Receptor ◽

Chemokine Receptors ◽

Binding Activity ◽

Receptor Expression ◽

Chemokine Production ◽

Chemokine Receptor Expression ◽

Cc Chemokine ◽

Primary Mouse ◽

Cxc Chemokine

Neuropeptides play an important role in the active communication between the nervous and immune systems. Substance P (SP) is a prominent neuropeptide involved in neurogenic inflammation and has been reported to exert various proinflammatory actions on inflammatory leukocytes including neutrophils. The present study further investigated the modulatory effect of SP (1 μM) on chemokine production and chemokine receptor expression in primary mouse neutrophils. Our results showed that SP primed neutrophils for chemotactic responses not only to the CXC chemokine macrophage inflammatory protein (MIP)-2/CXCL2 but also to the CC chemokine MIP-1α/CCL3. The activating effect of SP on neutrophils was further evidenced by upregulation of the CD11b integrin, the activation marker of neutrophils. SP induced both the mRNA and protein expression of the chemokines MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils and upregulated the chemokine receptors CC chemokine receptor (CCR)-1 and CXC chemokine receptor (CXCR)-2. This stimulatory effect on chemokine and chemokine receptor expression in neutrophils was further found to be neurokinin-1 receptor (NK-1R) specific. Pretreatment with selective NK-1R antagonists inhibited SP-triggered activation of neutrophils and chemokine and chemokine receptor upregulation. Moreover, SP-induced chemokine upregulation was NF-κB dependent. SP time dependently induced NF-κB p65 binding activity, IκBα degradation, and NF-κB p65 nuclear translocation in neutrophils. Inhibition of NF-κB activation with its inhibitor Bay11-7082 (10 μM) abolished SP-induced NF-κB binding activity and upregulation of MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils. Together, these results suggest that SP exerts a direct stimulatory effect on the expression of chemokines and chemokine receptors in mouse neutrophils. The effect is NK-1R mediated, involving NF-κB activation.

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CCR2+ Monocyte-Derived Ly6C-F4/80+ Fibrocytes Inhibit Collagen Degradation and Contribute to the Development of Colon Fibrosis Via Production of TIMP-1

Blood ◽

10.1182/blood-2018-99-118140 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3682-3682

Author(s):

Masahiro Masuya ◽

Naoki Kuroda ◽

Kensuke Hachiya ◽

Isao Tawara ◽

Yuki Kageyama ◽

...

Keyword(s):

Chemokine Receptor ◽

Chemokine Receptors ◽

Research Funding ◽

Collagen Degradation ◽

Type I ◽

Chimeric Mice ◽

Cc Chemokine ◽

Cxc Chemokine ◽

Chemokine Ligand ◽

Lp Cells

Abstract Introduction: Fibrocytes are derived from a subset of monocytes and express mesenchymal markers such as collagen type I (Col I) and hematopoietic markers such as CD45 and CD11b. They also express several chemokine receptors such as CC chemokine receptor (CCR)-1, CCR2, CCR5, CCR7, and CXC chemokine receptor type 4 (CXCR4). They circulate in the peripheral blood (PB) and can be isolated from many fibrotic tissues. Fibrocytes participate in both physiological wound healing and various pathological fibrosis including myelofibrosis, hypertrophic scar, systemic sclerosis, idiopathic pulmonary fibrosis, liver cirrhosis, and progressive kidney disease. In murine and human colitis, fibrocytes are also reported to be associated with the colon fibrosis. It has been described that migration of fibrocytes to the injured sites involves CC chemokine ligand 2 (CCL2)/CCR2 axis in the liver and kidney and CXC chemokine ligand 12 (CXCL12)/CXCR4 axis in the lung. However, there are few reports concerning the role of fibrocytes and their expression of chemokine receptors related to the induction of colon fibrosis. Methods: We generated bone marrow (BM) chimeric mice by transplantation of BM total-nucleated cells, which were isolated from enhanced green fluorescent protein (EGFP)-transgenic mice or CCR2 knockout (KO) mice, into lethally irradiated C57BL/6J-Ly5.1 mice. Two months after BM transplantation, BM chimeric mice were treated with a single intraperitoneal injection of azoxymethane (10 mg/kg body weight) followed by 3 cycles of 1% dextran sulfate sodium (DSS) in the drinking water. We assessed the level of fibrosis in the colon using Sirius red staining and analyzed the presence of BM-derived CD45+CD11b+Col I+ fibrocytes in the colon lamina propria (LP) using immunofluorescence staining and flow cytometry. Furthermore, we investigated the expressions of Col I, transforming growth factor-ß (TGF- ß), matrix metalloproteinases (MMPs), and tissue inhibitor of MMPs (TIMP)-1 in the colon tissues and fibrocytes sorted from colon LP cells after chronic DSS treatment using quantitative real-time RT-PCR. Results: During chronic inflammation, infiltration of CCR2+ BM-derived monocytes and fibrocytes and production of CCL2 in the colon were particularly increased and colon fibrosis was developed in EGFP BM chimeric mice. Two types of fibrocytes, CCR2+CXCR4+Ly6C-F4/80+ fibrocytes and CCR2-CXCR4+Ly6ChighF4/80- fibrocytes, were identified in the colon LP, whereas only the latter fibrocytes were detected in the PB. Adoptive transferred CCR2+Ly6ChighCol I- monocytes migrated to the injured colon and a part of them differentiated into CCR2+Col I+ fibrocytes. In CCR2KO BM chimeric mice, the numbers of monocytes and fibrocytes in the colon LP were significantly decreased and colon fibrosis was attenuated. However, there was no difference in the mRNA expressions of Col I, TGF-ß, and MMPs (MMP-1a, MMP-8, and MMP-13, known as collagenases) in colon tissues between EGFP BM chimeric mice and CCR2KO BM chimeric mice. Improvement of colon fibrosis in CCR2KO BM chimeric mice was associated with the decreased expression of Timp1 mRNA in colon tissues. We analyzed the expression of Timp1 mRNA in CCR2+ cells and CCR2- cells sorted from colon LP cells and found a high expression of Timp1 in CCR2+ monocytes/macrophages and fibrocytes. Conclusions: Circulating CCR2+ monocytes migrate into the inflamed colon via CCL2/CCR2 axis and differentiate into CCR2+Ly6C-F4/80+ fibrocytes, which inhibit collagen degradation and contribute to the development of colon fibrosis by the production of TIMP-1. Disclosures Masuya: Kyowa Hakko Kirin Co., Ltd.: Research Funding. Katayama:Ono Pharmaceutical: Research Funding; Novo Nordisk: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Toyama Chemical Co: Research Funding; Sysmex: Honoraria; Mochida Pharmaceutical Co. Ltd.,: Research Funding; Bristol-Myers Squibb: Honoraria; Astellas Pharma: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Takeda: Honoraria, Research Funding; Teijin Pharma: Research Funding; Eisai: Research Funding; Sumitomo Group: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Shire: Honoraria; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria; Taisho Toyama Pharma: Honoraria; Pfizer: Honoraria, Research Funding; Shionogi Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding.

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Down-regulation of neutrophil functions by the ELR+CXC chemokine platelet basic protein

Blood ◽

10.1182/blood.v96.9.2965 ◽

2000 ◽

Vol 96 (9) ◽

pp. 2965-2972 ◽

Cited By ~ 26

Author(s):

Jan E. Ehlert ◽

Andreas Ludwig ◽

Tobias A. Grimm ◽

Buko Lindner ◽

Hans-Dieter Flad ◽

...

Keyword(s):

Amino Acids ◽

Binding Sites ◽

Chemokine Receptors ◽

Cell Activation ◽

Basic Protein ◽

Cathepsin G ◽

Terminal Part ◽

Down Regulation ◽

Cxc Chemokine ◽

Continuous Accumulation

Abstract The platelet-derived neutrophil-activating peptide 2 (NAP-2, 70 amino acids) belongs to the ELR+ CXC subfamily of chemokines. Similar to other members of this group, such as IL-8, NAP-2 activates chemotaxis and degranulation in neutrophils (polymorphonuclear [PMN]) through chemokine receptors CXCR-1 and CXCR-2. However, platelets do not secrete NAP-2 as an active chemokine but as the C-terminal part of several precursors that lack PMN-stimulating capacity. As we have previously shown, PMN themselves may liberate NAP-2 from the precursor connective tissue-activating peptide III (CTAP-III, 85 amino acids) by proteolysis. Instead of inducing cell activation, continuous accumulation of the chemokine in the surroundings of the processing cells results in the down-regulation of specific surface-expressed NAP-2 binding sites and in the desensitization of chemokine-induced PMN degranulation. Thus, NAP-2 precursors may be regarded as indirect mediators of functional desensitization in neutrophils. In the current study we investigated the biologic impact of another major NAP-2 precursor, the platelet basic protein (PBP, 94 amino acids). We show that PBP is considerably more potent than CTAP-III to desensitize degranulation and chemotaxis in neutrophils. We present data suggesting that the high desensitizing capacity of PBP is based on its enhanced proteolytic cleavage into NAP-2 by neutrophil-expressed cathepsin G and that it involves efficient down-regulation of surface-expressed CXCR-2 while CXCR-1 is hardly affected. Correspondingly, we found PBP and, less potently, CTAP-III to inhibit CXCR-2– but not CXCR-1– dependent chemotaxis of neutrophils toward NAP-2. Altogether our findings demonstrate that the anti-inflammatory capacity of NAP-2 is governed by the species of its precursors.

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Hypoxia Modifies the Transcriptome of Primary Human Monocytes: Modulation of Novel Immune-Related Genes and Identification Of CC-Chemokine Ligand 20 as a New Hypoxia-Inducible Gene

The Journal of Immunology ◽

10.4049/jimmunol.177.3.1941 ◽

2006 ◽

Vol 177 (3) ◽

pp. 1941-1955 ◽

Cited By ~ 121

Author(s):

Maria Carla Bosco ◽

Maura Puppo ◽

Clara Santangelo ◽

Luca Anfosso ◽

Ulrich Pfeffer ◽

...

Keyword(s):

Human Monocytes ◽

Cc Chemokine ◽

Chemokine Ligand ◽

Immune Related Genes ◽

Cc Chemokine Ligand 20 ◽

Inducible Gene

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Down-regulation of neutrophil functions by the ELR+CXC chemokine platelet basic protein

Blood ◽

10.1182/blood.v96.9.2965.h8002965_2965_2972 ◽

2000 ◽

Vol 96 (9) ◽

pp. 2965-2972 ◽

Cited By ~ 1

Author(s):

Jan E. Ehlert ◽

Andreas Ludwig ◽

Tobias A. Grimm ◽

Buko Lindner ◽

Hans-Dieter Flad ◽

...

Keyword(s):

Amino Acids ◽

Binding Sites ◽

Chemokine Receptors ◽

Cell Activation ◽

Basic Protein ◽

Cathepsin G ◽

Terminal Part ◽

Down Regulation ◽

Cxc Chemokine ◽

Continuous Accumulation

The platelet-derived neutrophil-activating peptide 2 (NAP-2, 70 amino acids) belongs to the ELR+ CXC subfamily of chemokines. Similar to other members of this group, such as IL-8, NAP-2 activates chemotaxis and degranulation in neutrophils (polymorphonuclear [PMN]) through chemokine receptors CXCR-1 and CXCR-2. However, platelets do not secrete NAP-2 as an active chemokine but as the C-terminal part of several precursors that lack PMN-stimulating capacity. As we have previously shown, PMN themselves may liberate NAP-2 from the precursor connective tissue-activating peptide III (CTAP-III, 85 amino acids) by proteolysis. Instead of inducing cell activation, continuous accumulation of the chemokine in the surroundings of the processing cells results in the down-regulation of specific surface-expressed NAP-2 binding sites and in the desensitization of chemokine-induced PMN degranulation. Thus, NAP-2 precursors may be regarded as indirect mediators of functional desensitization in neutrophils. In the current study we investigated the biologic impact of another major NAP-2 precursor, the platelet basic protein (PBP, 94 amino acids). We show that PBP is considerably more potent than CTAP-III to desensitize degranulation and chemotaxis in neutrophils. We present data suggesting that the high desensitizing capacity of PBP is based on its enhanced proteolytic cleavage into NAP-2 by neutrophil-expressed cathepsin G and that it involves efficient down-regulation of surface-expressed CXCR-2 while CXCR-1 is hardly affected. Correspondingly, we found PBP and, less potently, CTAP-III to inhibit CXCR-2– but not CXCR-1– dependent chemotaxis of neutrophils toward NAP-2. Altogether our findings demonstrate that the anti-inflammatory capacity of NAP-2 is governed by the species of its precursors.

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