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C-C Chemokine Receptors
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
Kuldeep Neote, Shaun R. McColl
In sharp contrast to CXC chemokine receptors where only two receptor subtypes account for binding of all the different CXC chemokines, there are at least 4 different C-C chemokines receptors that have been identified by molecular cloning. Pharmacological characterization of chemokine receptors has implied that there are not more then 4 receptor subtypes on different subpopulations of leukocytes. However, preliminary characterization of the cloned C-C chemokine receptors suggests that different receptor subtypes have the capacity to interact with identical ligands. This implies that effector cells will only respond to a given chemokine if a particular receptor is expressed in that cell. This feature might explain why some C-C chemokines have a preference for a specific subset of leukocytes. Alternatively, the temporal and spatial expression of chemokine expression could dictate the homing and preferential migration of leukocytes to areas of immune reactivity. With the availability of cloned receptors, structure/function analysis should define motifs important for chemokine binding and coupling to signal transduction pathways. Furthermore, a better understanding of the expression and biochemical and pharmacological characteristics of a given C-C chemokine receptor will soon be unraveled. These types of avenues will be crucial in understanding how ligand binding leads to receptor activation and eventually cell motility and activation.
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).
Airway Epithelial and Early Innate Immune Responses toVirus Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Alan Chen-Yu Hsu, Su-Ling Loo, Faezeh Fathi Aghdam, Kristy Parsons, Philip M. Hansbro, Peter A. B. Wark
Neutrophils are also the phagocytic cells that ingest invading viruses via similar mechanisms to those that occur in macrophages.71 Upon infection, neutrophils infiltrate into the airways via neutrophil surface receptors CXC chemokine receptor (CXCR) 1 and 2, and migrate down a chemotactic gradient of CXCL-8 produced by infected cells.72 Once the infected cells are phagocytosed and incorporated into phagolysosomes, neutrophil elastases, matrix metalloproteases (MMPs), and myeloperoxidase (MPO) are produced to convert reactive oxygen species (ROS) such as hydrogen peroxide into hypochlorous acid that digest viral proteins.65,66,73,74 This process is called the neutrophil oxidative burst and is now considered as a defensive response against respiratory viruses. Neutrophils can also be infected with viruses and produce inflammatory cytokines such as CXL-8 and TNF-α that then further enhance inflammatory responses in the lung.75–77 Neutrophils produce SP-D protein that directly binds to influenza HA and adenovirus surface capsid protein, after which human neutrophil peptides (HNP) 1 and 2 then bind to the viral surface protein-SP-D complex that enhances phagocytosis.78–82
Rongjin Niantong Fang ameliorates cartilage degeneration by regulating the SDF-1/CXCR4-p38MAPK signalling pathway
Published in Pharmaceutical Biology, 2022
Jun Chen, Nan Chen, Ting Zhang, Jie Lin, Yunmei Huang, Guangwen Wu
Specific binding of chemokine SDF-1 to CXC chemokine receptor family member CXCR4 exerts multiple biological effects. Experimental studies have shown that the binding of SDF-1 to CXCR4 leads to the degradation the of chondrocyte matrix by inducing the secretion of MMPs (Mazzetti et al. 2004; Lisignoli et al. 2006; Wei et al. 2006; Guang et al. 2012; Dong et al. 2016; Lu et al. 2016; Chen et al. 2017). As one of the important signalling pathways in eukaryotic cells, MAPK pathway regulates cell structure and function (Pawig et al. 2015). p38, an important component in the MAPK pathway, is closely related to cartilage degeneration OA and has the strongest effect on cartilage destruction. Activation of p38 can induce the secretion of chondrocyte MMPs, degrade the extracellular matrix, induce chondrocyte hypertrophy, mediate the inflammatory response, cell apoptosis, and other effects (Prasadam et al. 2012).
Discovery and characterization of a neutralizing pan-ELR+CXC chemokine monoclonal antibody
Published in mAbs, 2020
Jeffrey S. Boyles, Catherine B. Beidler, Beth A. Strifler, Daniel S. Girard, Zhanna Druzina, Jim D. Durbin, Michelle L. Swearingen, Linda N. Lee, Kristine Kikly, Sudhakar Chintharlapalli, Derrick R. Witcher
The CXC chemokine receptors 1 and 2 (CXCR1 and CXCR2) are G-protein coupled receptors (GPCR) expressed on granulocytes, monocytes, mast cells, and some natural killer cells that are capable of activating multiple downstream signaling pathways.1,2 Chemokines have been classified into 4 subfamilies, based on the presence of cysteines at the amino terminal: CXC, CC, CX3C and C.3,4 Among chemokine subfamilies, CXC chemokines can be further subclassified into Glu-Leu-Arg (ELR+) and ELR− CXC chemokines based on the presence or absence of a tripeptide ELR motif at the amine terminus. The ligands for CXCR1 and CXCR2 make up the ELR+CXC chemokine family. Despite the conserved structure and shared receptors, these chemokines share very little sequence homology outside of the ELRCXC motif (Figure 1). In humans, CXCL6 and CXCL8 signal through CXCR1, while all seven chemokines (CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8) signal through CXCR2.5 Chemokine affinities to the receptors are in the single-digit nM range, and they typically have short turnover rates as they rapidly bind receptor, internalize, and are degraded.6,7 Characteristic of ELR+CXC chemokines is their ability to specifically recruit neutrophils into inflamed tissues.
Expression signature, prognosis value, and immune characteristics of Siglec-15 identified by pan-cancer analysis
Published in OncoImmunology, 2020
Baihui Li, Bailu Zhang, Xuezhou Wang, Ziqing Zeng, Ziqi Huang, Lin Zhang, Feng Wei, Xiubao Ren, Lili Yang
Siglecs on macrophages and DCs could modulate toll-like receptor-induced cytokine responses.45,61,62The pathway analysis also suggested that Siglec15 was related to activation of the chemokine signaling pathway. CXC chemokine receptor CXCR3 is mainly expressed in Treg, B cells, and tumor cells.63,64 There is an increasing trend for CXCR3 and MMP9 in patients with overexpressed Siglec-15, which may recruit Treg.65 Our data analysis demonstrated that Siglec-15 was significantly associated with Tregs infiltration in cancers from TCGA and positively associated with FoxP3 in LUAD tissues by RT-qPCR. This may result in a specific TreghighSiglec15high TME. These results indicate that Siglec-15 may exist in an “immune-excluded” environment, which is consistent with more Tregs and higher TGF-β signaling.66 Therefore, application of anti-Siglec-15 antibody after other therapeutic interventions may hold promise.