Chemokine and Chemokine Receptor Dynamics during Genital Chlamydial Infection

ABSTRACT Current design strategies for vaccines against certain microbial pathogens, including Chlamydia trachomatis, require the induction and targeting of specific immune effectors to the local sites of infection known as the mucosal effector sites. Chemokines and their receptors are important mediators of leukocyte trafficking and of the controlled recruitment of specific leukocyte clonotypes during host defense against infections and during inflammation. We analyzed the dynamics of chemokine and chemokine receptor expression in genital mucosae during genital chlamydial infection in a murine model to determine how these molecular entities influence the development of immunity and the clearance of infection. A time course study revealed an increase of up to threefold in the levels of expression of RANTES, monocyte chemotactic protein 1 (MCP-1), gamma-interferon-inducible protein 10 (IP-10), macrophage inflammatory protein 1α (MIP-1α), and intercellular adhesion molecule type 1 (ICAM-1) after genital infection with the C. trachomatis agent of mouse pneumonitis. Peak levels of expression of RANTES, MCP-1, and MIP-1α occurred by day 7 after primary infection, while those of IP-10 and ICAM-1 peaked by day 21. Expression levels of these molecules decreased by day 42 after primary infection, by which time all animals had resolved the infection, suggesting an infection-driven regulation of expression. A rapid upregulation of expression of these molecules was observed after secondary infection. The presence of cells bearing the chemokine receptors CCR5 and CXCR3, known to be preferentially expressed on Th1 and dendritic cells, was also synchronous with the kinetics of immune induction in the genital tract and clearance of infection. Results demonstrated that genital chlamydial infection is associated with a significant induction of chemokines and chemokine receptors that are involved in the recruitment of Th1 cells into the site of infection. Future studies will focus on how selective modulation of chemokines and their receptors can be used to optimize long-term immunity against Chlamydia.

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Biphasic Expression of Atypical Chemokine Receptor (ACKR) 2 and ACKR4 in Colorectal Neoplasms in Association with Histopathological Findings

Biomolecules ◽

10.3390/biom11010008 ◽

2020 ◽

Vol 11 (1) ◽

pp. 8

Author(s):

Paulina Lewandowska ◽

Jaroslaw Wierzbicki ◽

Marek Zawadzki ◽

Anil Agrawal ◽

Małgorzata Krzystek-Korpacka

Keyword(s):

Lymph Node ◽

Lymph Node Metastasis ◽

Chemokine Receptor ◽

Growth Pattern ◽

Chemokine Receptors ◽

Receptor Expression ◽

Transcriptional Analysis ◽

Neoplastic Tissue ◽

Node Metastasis ◽

Affected Tissue

Facilitating resolution of inflammation using atypical chemokine receptors (ACKR) as an anticancer strategy is considered but requires a deeper understanding of receptor role in carcinogenesis. We aimed at transcriptional analysis (RTqPCR) of ACKR2 and ACKR4 expression in colorectal adenoma-adenocarcinoma sequence in paired normal-neoplastic tissues from 96 polyps and 51 cancers. On average, ACKR2 was downregulated in neoplastic as compared to non-affected tissue in polyp (by 2.7-fold) and cancer (by 3.1-fold) patients. The maximal downregulation (by 8.2-fold) was observed in adenomas with the highest potential for malignancy and was gradually lessening through cancer stages I-IV, owing to increased receptor expression in tumors. On average, ACKR4 was significantly downregulated solely in adenocarcinomas (by 1.5-fold), less so in patients with lymph node metastasis, owing to a gradual decrease in ACKR4 expression among N0-N1-N2 cancers in non-affected tissue without changes in tumors. In adenomas, ACKR4 downregulation in neoplastic tissue increased with increasing potential for malignancy and contribution of villous growth pattern. ACKR4 expression increased in non-affected tissue with a concomitant decrease in pathological mucosa. In conclusion, the changes in ACKRs expression occur already in precancerous colorectal lesions, culminating in the adenomas with the highest potential for malignancy. Therefore, chemoprevention by manipulating ACKRs’ expression is worth exploration.

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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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E-protein–regulated expression of CXCR4 adheres preselection thymocytes to the thymic cortex

Journal of Experimental Medicine ◽

10.1084/jem.20182285 ◽

2019 ◽

Vol 216 (8) ◽

pp. 1749-1761 ◽

Cited By ~ 1

Author(s):

Tejas Kadakia ◽

Xuguang Tai ◽

Michael Kruhlak ◽

Jan Wisniewski ◽

Il-Young Hwang ◽

...

Keyword(s):

Transcription Factors ◽

Chemokine Receptor ◽

Chemokine Receptors ◽

Cxcr4 Expression ◽

Receptor Expression ◽

Thymic Epithelial Cells ◽

E Protein ◽

Regulated Expression ◽

Genes Encoding ◽

Protein Transcription

Preselection thymocytes are normally retained in the thymic cortex, but the mechanisms responsible remain incompletely understood. We now report that deletion of genes encoding the E-protein transcription factors E2A and HEB disorders chemokine receptor expression on developing thymocytes to allow escape of preselection TCR−CD8+ thymocytes into the periphery. We document that CXCR4 expression normally anchors preselection thymocytes to the thymic cortex via interaction with its ligand CXCL12 on cortical thymic epithelial cells, and that disruption of CXCR4–CXCL12 engagements release preselection thymocytes from the thymic cortex. We further document that CXCR4 expression must be extinguished by TCR-mediated positive selection signals to allow migration of TCR-signaled thymocytes out of the thymic cortex into the medulla. Thus, E-protein transcription factors regulate the ordered expression pattern of chemokine receptors on developing thymocytes, and the interaction of the chemokine receptor CXCR4 with its ligand adheres TCR-unsignaled preselection thymocytes to the thymic cortex.

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Coreceptor/Chemokine Receptor Expression on Human Hematopoietic Cells: Biological Implications for Human Immunodeficiency Virus–Type 1 Infection

Blood ◽

10.1182/blood.v93.4.1145 ◽

1999 ◽

Vol 93 (4) ◽

pp. 1145-1156 ◽

Cited By ~ 67

Author(s):

Benhur Lee ◽

Janina Ratajczak ◽

Robert W. Doms ◽

Alan M. Gewirtz ◽

Mariusz Z. Ratajczak

Keyword(s):

Chemokine Receptor ◽

Chemokine Receptors ◽

Hematopoietic Cells ◽

Receptor Expression ◽

Chemokine Receptor Expression ◽

Cd34 Cells ◽

Immunodeficiency Virus ◽

Γ Interferon ◽

Hiv 1

Abstract The recent discovery of chemokine receptors as coreceptors for human immunodeficiency virus–type 1 (HIV-1) entry offers new avenues for investigating the pathogenesis of acquired immunodeficiency syndrome (AIDS)-related cytopenias. To this end, we sought to (1) phenotype human hematopoietic cells for CD4 and the HIV-1 coreceptors CXCR4, CCR5, CCR3, and CCR2b; (2) correlate CD4 and chemokine receptor expression with their susceptibility to HIV-1 infection; and (3) examine any potential interplay between inflammatory cytokines released during HIV-1 infection and regulation of chemokine receptor expression. Fluorescence-activated cell sorting (FACS) analysis of bone marrow mononuclear cells (BMMNC), cells derived from serum-free expanded hematopoietic lineages (colony-forming unit–granulocyte-macrophage [CFU-GM], colony-forming unit-megakaryocyte [CFU-Meg], and burst-forming unit-erythroid [BFU-E]), and CD34+ cells showed differential expression of chemokine receptors and CD4 with some lineage specificity. Significantly, FACS-sorted CXCR4+/CD34+ cells had the same clonogeneic potential as CXCR4−/CD34+ cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of FACS-sorted human candidate stem cells (HSC; CD34+, c-kit+, Rho123low) showed the presence of CXCR4 mRNA but not CD4 mRNA. Infection studies with HIV-1 Env-pseudotyped luciferase reporter viruses indicated that X4 Env (CXCR4-using) pseudotypes infected megakaryocytic cells, whereas R5 Env (CCR5-using) pseudotypes did not. Similarly, R5 but not X4 Env-pseudotyped viruses infected granulocyte-macrophage cells in a CD4/CCR5-dependent manner. Erythroid cells were resistant to R5 or X4 viral infection. Finally, we found that γ-interferon treatment upregulated CXCR4 expression on primary hematopoietic cells. In summary, the delineation of chemokine receptor expression on primary hematopoietic cells is a first step towards dissecting the chemokine-chemokine receptor axes that may play a role in hematopoietic cell proliferation and homing. Furthermore, susceptibility of hematopoietic cells to HIV-1 infection is likely to be more complicated than the mere physical presence of CD4 and the cognate chemokine receptor. Lastly, our results suggest a potential interplay between γ-interferon secretion and CXCR4 expression.

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Coreceptor/Chemokine Receptor Expression on Human Hematopoietic Cells: Biological Implications for Human Immunodeficiency Virus–Type 1 Infection

Blood ◽

10.1182/blood.v93.4.1145.404k17_1145_1156 ◽

1999 ◽

Vol 93 (4) ◽

pp. 1145-1156 ◽

Cited By ~ 3

Author(s):

Benhur Lee ◽

Janina Ratajczak ◽

Robert W. Doms ◽

Alan M. Gewirtz ◽

Mariusz Z. Ratajczak

Keyword(s):

Chemokine Receptor ◽

Chemokine Receptors ◽

Hematopoietic Cells ◽

Receptor Expression ◽

Chemokine Receptor Expression ◽

Cd34 Cells ◽

Immunodeficiency Virus ◽

Γ Interferon ◽

Hiv 1

The recent discovery of chemokine receptors as coreceptors for human immunodeficiency virus–type 1 (HIV-1) entry offers new avenues for investigating the pathogenesis of acquired immunodeficiency syndrome (AIDS)-related cytopenias. To this end, we sought to (1) phenotype human hematopoietic cells for CD4 and the HIV-1 coreceptors CXCR4, CCR5, CCR3, and CCR2b; (2) correlate CD4 and chemokine receptor expression with their susceptibility to HIV-1 infection; and (3) examine any potential interplay between inflammatory cytokines released during HIV-1 infection and regulation of chemokine receptor expression. Fluorescence-activated cell sorting (FACS) analysis of bone marrow mononuclear cells (BMMNC), cells derived from serum-free expanded hematopoietic lineages (colony-forming unit–granulocyte-macrophage [CFU-GM], colony-forming unit-megakaryocyte [CFU-Meg], and burst-forming unit-erythroid [BFU-E]), and CD34+ cells showed differential expression of chemokine receptors and CD4 with some lineage specificity. Significantly, FACS-sorted CXCR4+/CD34+ cells had the same clonogeneic potential as CXCR4−/CD34+ cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of FACS-sorted human candidate stem cells (HSC; CD34+, c-kit+, Rho123low) showed the presence of CXCR4 mRNA but not CD4 mRNA. Infection studies with HIV-1 Env-pseudotyped luciferase reporter viruses indicated that X4 Env (CXCR4-using) pseudotypes infected megakaryocytic cells, whereas R5 Env (CCR5-using) pseudotypes did not. Similarly, R5 but not X4 Env-pseudotyped viruses infected granulocyte-macrophage cells in a CD4/CCR5-dependent manner. Erythroid cells were resistant to R5 or X4 viral infection. Finally, we found that γ-interferon treatment upregulated CXCR4 expression on primary hematopoietic cells. In summary, the delineation of chemokine receptor expression on primary hematopoietic cells is a first step towards dissecting the chemokine-chemokine receptor axes that may play a role in hematopoietic cell proliferation and homing. Furthermore, susceptibility of hematopoietic cells to HIV-1 infection is likely to be more complicated than the mere physical presence of CD4 and the cognate chemokine receptor. Lastly, our results suggest a potential interplay between γ-interferon secretion and CXCR4 expression.

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Chemokine receptors and their role in inflammation and infectious diseases

Blood ◽

10.1182/blood.v95.10.3032.010k17_3032_3043 ◽

2000 ◽

Vol 95 (10) ◽

pp. 3032-3043 ◽

Cited By ~ 41

Author(s):

Craig Murdoch ◽

Adam Finn

Keyword(s):

Infectious Diseases ◽

Chemokine Receptor ◽

Intracellular Signaling ◽

Chemokine Receptors ◽

Cell Activation ◽

Cell Types ◽

Receptor Expression ◽

Chemokine Receptor Expression ◽

Disease States ◽

Receptor Biology

Chemokines are small peptides that are potent activators and chemoattractants for leukocyte subpopulations and some nonhemopoietic cells. Their actions are mediated by a family of 7-transmembrane G-protein–coupled receptors, the size of which has grown considerably in recent years and now includes 18 members. Chemokine receptor expression on different cell types and their binding and response to specific chemokines are highly variable. Significant advances have been made in understanding the regulation of chemokine receptor expression and the intracellular signaling mechanisms used in bringing about cell activation. Chemokine receptors have also recently been implicated in several disease states including allergy, psoriasis, atherosclerosis, and malaria. However, most fascinating has been the observation that some of these receptors are used by human immunodeficiency virus type 1 in gaining entry into permissive cells. This review will discuss structural and functional aspects of chemokine receptor biology and will consider the roles these receptors play in inflammation and in infectious diseases.

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Up-regulation of the chemokine receptor CCR7 in classical but not in lymphocyte-predominant Hodgkin disease correlates with distinct dissemination of neoplastic cells in lymphoid organs

Blood ◽

10.1182/blood.v99.4.1109 ◽

2002 ◽

Vol 99 (4) ◽

pp. 1109-1116 ◽

Cited By ~ 77

Author(s):

Uta E. Höpken ◽

Hans-Dieter Foss ◽

Dagmar Meyer ◽

Michael Hinz ◽

Korinna Leder ◽

...

Keyword(s):

Cell Lines ◽

Chemokine Receptor ◽

Chemokine Receptors ◽

Critical Role ◽

Receptor Expression ◽

Hodgkin Disease ◽

Lymphoid Tissues ◽

Neoplastic Cells ◽

Chemokine Receptor Expression ◽

Target Organs

Chemokines and chemokine receptors are key mediators for regulating cell traffic and positioning in both homeostatic and inflammatory conditions. It is also presumed that chemokines and their receptors are likely to play a critical role in the localization of malignant hematopoietic cells in their target organs. This study analyzed chemokine and chemokine receptor expression in several Hodgkin disease (HD)–derived cell lines and in HD tumors. All HD-derived cell lines expressed functional CCR7 and CXCR4 receptors. CCR7 up-regulation was mediated by constitutive NF-κB activity. Lymphoid tissues in HD revealed differential expression levels of CCR7, CXCR4, and CXCR5, depending on the distinct subtypes of HD. HD of the classical subtypes, predominantly located in the interfollicular zone, showed strong CCR7 and CXCR4 expression and moderate CXCR5 expression. In contrast, the nodular lymphocyte-predominant HD (NLP) subtype, regularly associated with follicular structures, exhibited no CCR7 reactivity but abundant CXCR4 staining. Their respective chemokine ligands showed marked expression by reactive cells within the tumors of classical HD and outside of the tumor nodules in NLPHD. Functionally, such differential chemokine receptor expression might contribute to specific localization and confinement of neoplastic cells within the target organs in the distinct HD entities.

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Expression pattern of T-cell–associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma

Blood ◽

10.1182/blood.v96.2.685 ◽

2000 ◽

Vol 96 (2) ◽

pp. 685-690 ◽

Cited By ~ 101

Author(s):

Dan Jones ◽

Carl O'Hara ◽

Madeleine D. Kraus ◽

Antonio R. Perez–Atayde ◽

Aliakbar Shahsafaei ◽

...

Keyword(s):

T Cell ◽

Hodgkin Lymphoma ◽

Chemokine Receptor ◽

Chemokine Receptors ◽

Cell Lymphoma ◽

Large Cell ◽

T Cell Lymphoma ◽

Receptor Expression ◽

Non Hodgkin Lymphoma ◽

Alk Positive

Abstract Chemokine receptors mediate the migration of lymphocytes through the binding of soluble ligands, and their expression is differentially regulated in lymphocyte subsets. The pattern of chemokine receptor expression in T-cell non-Hodgkin lymphoma has not been previously studied. Using a panel of mouse monoclonal antibodies, we studied the immunohistochemical expression of the Th1-associated chemokine receptor CXCR3 in 141 patients with T-cell lymphoma, and we studied the receptors CCR4 and CCR5 and some of their ligands in a subset of these tumors. Expression of CXCR3 was typical of the smaller T cells in angioimmunoblastic lymphoma (15 of 18 patients), angiocentric lymphoma (3 of 3 patients), histiocyte-rich tumors (4 of 5 patients), and unspecified T-cell lymphomas (17 of 39 patients). CXCR3 expression was seen in only 1 of 15 patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma. In contrast, all ALK-positive tumors showed diffuse reactivity for the Th2-associated receptor CCR4 (5 of 5 patients). CCR4 expression was also a consistent feature of the large-cell transformation of mycosis fungoides. CCR5 expression showed no consistent association with any T-cell tumor type. The chemokines Mig (CXCR3 ligand), TARC (CCR4 ligand), and MCP-2 (CCR5 ligand) were detected in intratumoral blood vessels and histiocytes. Mig was also coexpressed by a subset of CXCR3-positive tumor cells in 6 of 20 lymphomas. MCP-2 was highly expressed in stromal cells in 3 patients with nodal involvement by cutaneous T-cell lymphoma. As with normal T-cell subsets, we demonstrated that there is frequent differential expression of chemokine receptors in T-cell tumors, which may explain, in part, the distinctive patterns of spread in different tumor subtypes.

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Association of haemolytic uraemic syndrome with dysregulation of chemokine receptor expression in circulating monocytes

Clinical Science ◽

10.1042/cs20150016 ◽

2015 ◽

Vol 129 (3) ◽

pp. 235-244 ◽

Cited By ~ 4

Author(s):

Maria Victoria Ramos ◽

Matias Ruggieri ◽

Analia Cecilia Panek ◽

Maria Pilar Mejias ◽

Romina Jimena Fernandez-Brando ◽

...

Keyword(s):

Chemokine Receptor ◽

Chemokine Receptors ◽

Haemolytic Uraemic Syndrome ◽

Receptor Expression ◽

Acute Period ◽

Chemokine Receptor Expression

The expression of the chemokine receptors CCR1, CCR2 and CCR5 in circulating monocytes, taken from patients with the haemolytic uraemic syndrome during their acute period, is increased, accompanied by loss of functionality. This dysregulation of monocytes suggested that the chemokine pathway could participate in HUS development.

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Rat Cytomegalovirus Virion-Associated Proteins R131 and R129 Are Necessary for Infection of Macrophages and Dendritic Cells

Pathogens ◽

10.3390/pathogens9110963 ◽

2020 ◽

Vol 9 (11) ◽

pp. 963

Author(s):

Iris K. A. Jones ◽

Nicole N. Haese ◽

Philippe Gatault ◽

Zachary J. Streblow ◽

Takeshi F. Andoh ◽

...

Keyword(s):

Dendritic Cells ◽

Chemokine Receptor ◽

Viral Entry ◽

Chemokine Receptors ◽

Bone Marrow Cells ◽

Organ Transplant ◽

Receptor Expression ◽

In Vivo Model ◽

Solid Organ

Cytomegalovirus (CMV) establishes persistent, latent infection in hosts, causing diseases in immunocompromised patients, transplant recipients, and neonates. CMV infection modifies the host chemokine axis by modulating chemokine and chemokine receptor expression and by encoding putative chemokine and chemokine receptor homologues. The viral proteins have roles in cellular signaling, migration, and transformation, as well as viral dissemination, tropism, latency and reactivation. Herein, we review the contribution of CMV-encoded chemokines and chemokine receptors to these processes, and further elucidate the viral tropism role of rat CMV (RCMV) R129 and R131. These homologues of the human CMV (HCMV)-encoded chemokines UL128 and UL130 are of particular interest because of their dual role as chemokines and members of the pentameric entry complex, which is required for entry into cell types that are essential for viral transmission and dissemination. The contributions of UL128 and UL130 to acceleration of solid organ transplant chronic rejection are poorly understood, and are in need of an effective in vivo model system to elucidate the phenomenon. We demonstrated similar molecular entry requirements for R129 and R131 in the rat cells, as observed for HCMV, and provided evidence that R129 and R131 are part of the viral entry complex required for entry into macrophages, dendritic cells, and bone marrow cells.

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