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Viral Chemokine Receptors
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
Philip M. Murphy, Sunil K. Ahuja, Ji-Liang Gao
Two types of human MCP-1 receptors have been cloned and functionally expressed in frog oocytes.9 Their sequences differ only in the carboxy-terminal intracellular segment after residue 313, presumably due to alternative splicing of the same gene. However, the complete ORF of MCP-1 receptor type B lacks any intervening sequence in genomic DNA.40 Overall, both MCP-1 receptor A and B are -54% identical in amino acid sequence to the MIP-1α/RANTES receptor, yet neither MIP-1α nor RANTES is an effective calcium mobilizing agonist when they are expressed in frog oocytes. Direct radioligand binding to the MCP-1 receptors and their signaling properties in transfected mammalian cells has not yet been reported. The sequences and functional properties of mammalian and viral CC chemokine receptors may be useful for targeting residues that are critical for restricting the selectivity of these receptors to CC chemokines. However, no site-directed mutagenesis studies have been reported yet.
Chemokines and Chemokine Receptor Interactions and Functions
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
Philip L. Shields, David H. Adams
Chemokines act via specific cell surface, seven transmembrane spanning G-protein-linked receptors (Figure 2). Five CXC chemokine receptors (CXCR1 to CXCR5), ten CC chemokine receptors (CCR1 to CCR10), and one CXXXC receptor have been identified so far in humans (Table 1). Most chemokine receptors are shared by more than one chemokine, such as CXCR3 which binds IP-10, MIG or IFN-inducible T cell alpha chemoattractant (I-TAC). A few have a restricted number of ligands such as CCR6 which binds MEP-3α and CXCR1, which binds IL-8 and granulocyte chemoattractant protein-2 (GCP-2). Some chemokines can also interact with more than one receptor (e.g., MIP-1α) suggesting a degree of redundancy and flexibility in the chemokine/chemokine receptor system. Engagement of chemokine receptors is associated with a calcium flux and G-protein dependent activation of phospholipases. The details of the downstream signals differ between cell types, so, for instance, IL-8 causes phospholipase D activation in lymphocytes, but not in neutrophils. There is also evidence that the consequences of receptor engagement is determined by the intracellular signals., Thus cytoskeletal rearrangement is a consequence of phospholipase C and Rho activation, whereas activation of protein tyrosine kinases is involved in cell activation and proliferation (11).
The immune response to fungal challenge
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Jeffery Hu, Jeffery J. Auletta
Macrophages are another key effector cell in the defense against fungal infection. They have a particular role in controlling disseminated fungal infection and are recruited to site of infection through chemokine receptors. Polymorphism in genes that decrease CX3C chemokine receptor 1 function found on monocytes revealed increased susceptibility to disseminated infection but not mucosal infection [44,45]. Additionally, deficiency in CC-chemokine receptor 2 in murine models also demonstrated increased susceptibility to disseminated infection. [46]. Monocytes and macrophages play an important role in “innate immunity” or “trained immunity.” This has been demonstrated in studies performed in which mice previously exposed to attenuated strains of C. albicans were protected from invasive candidiasis in subsequent fungal challenge [47]. Such immunity was thought to have been mediated by epigenetic reprogramming of innate immune cells allowing for enhanced production of proinflammatory cytokines [48]. Clinical relevance of trained immunity has been suggested by reports of defective trained immunity in patients with chronic mucocutaneous candidiasis and points to new therapeutic approaches to vaccinations [49].
CCR5 is a potential therapeutic target for cancer
Published in Expert Opinion on Therapeutic Targets, 2021
Hossein Hemmatazad, Martin D. Berger
Chemokine receptors mediate the interaction between chemokines and different immune cell types and comprise a large family of seven transmembrane domain G-protein-coupled receptors [16]. These chemokine receptors are classified according to the subgroup of chemokines they bind (CXCR, CCR, XCR, CX3CR) [17]. Every single receptor can be either activated by one or many different chemokines with various affinity, efficacy and downstream cellular responses [18]. In 1996, Samson et al. cloned the ChemR13 human gene, characterizing a new CC chemokine receptor [19]. This new CC chemokine receptor was designated as CC-CKR5, as it was the fifth functionally identified receptor in its class and responded physiologically to macrophage inflammatory protein-1α (MIP-1α or CCL3), MIP-1β (or CCL4) and regulated on activation normal T cell expressed and secreted protein (RANTES or CCL5) [19]. Figure 1 illustrates the plethora of chemokines with binding affinity to CCR5 exerting both agonistic (right) and antagonistic effects (left).
Multi-drug approaches to NASH: what’s in the development pipeline?
Published in Expert Opinion on Investigational Drugs, 2020
Michael P Johnston, Janisha Patel, Christopher D Byrne
For many of the therapeutic agents studied in NASH, the anti-inflammatory and antifibrotic mechanisms are inextricably linked. Their combined improvement is the primary endpoint in many relevant drug trials. Downregulation of migration and infiltration of monocytes, macrophages, and collagen-promoting hepatic stellate cells formed the basis of the theory behind the rationale for the CENTAUR trial. Antagonism of the CC chemokine receptor types 2 and 5 (CCR2/CCR5) by cenicriviroc targeted anti-inflammatory and antifibrotic mechanisms thought to be beneficial in the amelioration of NASH [20]. CENTAUR was a randomized placebo-controlled trial of 289 patients with NASH who had a NAS ≥ 4 and liver fibrosis stages 1–3. The primary outcome was a ≥2 point improvement in NAS with no worsening of fibrosis at 1 year. Disappointingly, there was not a significant difference in the primary outcome between the study drug cenicriviroc and placebo (16% vs. 19%). However, the secondary outcome of fibrosis improvement alone attributable to cenicriviroc was met (20% of patients benefitting in the treatment arm vs. 10% in the placebo arm) [20]. Furthermore, no improvement in the metabolic profile was seen in the intervention arm, despite the theory that decreasing macrophage recruitment into adipose tissue via CCR2 antagonism could benefit insulin resistance. There is an active phase II trial of cenicriviroc as combination therapy with the FXR agonist tropifexor in patients with NASH and F2/F3 fibrosis (NCT03517540).
Association of genetic polymorphisms of chemokines and their receptors with clearance or persistence of hepatitis C virus infection
Published in British Journal of Biomedical Science, 2019
M El-Bendary, M Neamatallah, H Elalfy, T Besheer, M El-Setouhy, MM Youssef, M Zein, D Elhammady, A Hegazy, G Esmat
Chemokines belong to a family of small chemotactic glycoproteins measuring 8–12 kDa that control cell recruitment [3]. Based on the circumstances under which their expression is dependent, chemokines are usually referred to as either homeostatic or pro-inflammatory [4]. The latter initiate the signalling pathways by which leukocytes undergo migration and extrusion from blood into tissues through ligation with their cognate receptors [5]. Hence, chemokines and chemokine receptors are the primary factors involved in leukocyte aggregation at immune response sites. Four main subfamilies comprise the broader family of chemokines: CXC (α), CC (β), XC (γ) and CX3C (δ) [6,7]. Expression of CC chemokine receptor type 2 (CCR2) occurs predominantly on macrophages and monocytes, as well as dendritic cells (DCs) and T cells. Ligands for CCR2 include CCL2, also known as monocyte chemotactic protein-1, CCL7, CCL8 and CCL13. While all these ligands are widely expressed in a hepatic setting, livers of HCV-infected patients have significantly increased transcription levels of CCR2 and CCL2 mRNA [8].