Chemokines
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P137-139
2025-10-23
52
Chemokines (a clipping blend of chemotactic cytokines) are critical molecular messengers in the complex cellular communication network used by the immune system. Almost 50 human chemokine genes have been identified to date. The two major subclasses of chemokines are designated CC- or CXC-, reflecting the relative position of the two proximal to the N-terminus canonical cysteines, being either adjacent or separated by a single amino acid, respectively. XCL1 and XCL2, and CX3CL1 represent additional structural chemokine forms with one cysteine and three amino acids between the two canonical cysteines, respectively. CX3CL1 and another chemokine, CXCL16, are associated with a cell membrane via a long spacer sequence and anchored by a transmembrane domain; however, both these chemokines can be cleaved off their stalks and give rise to functional soluble molecules. All other chemokines are secreted proteins of 67 to 127 amino acids. Historically, chemokines have been grouped into functional subfamilies termed inflammatory and homeostatic chemokines. Former are induced by inflammatory signals and control the recruitment of effector leukocytes in infection, inflammation, tissue injury, and malignancies, whereas those belonging to the latter group navigate leukocytes during hematopoiesis in the BM and in the thymus, during initiation of adaptive immune responses in SLOs and in immune surveillance of healthy peripheral tissues. However, it is now clear that such functional distinction is largely blurred, as many “inflammatory” chemokines are produced under physiologic conditions and the expression of “homeostatic” chemokines is upregulated in inflammation.
Chemokine signals are transmitted through specific cell-surface G protein-coupled receptors (GPCRs) with seven transmembrane domains. The human chemokine receptor repertoire identified at present consists of 20 different GPCRs The tremendous specificity and plasticity of leukocyte homing and tissue localization is largely determined by the interactions of chemokines with their cognate receptors. Individual leukocyte subsets express highly characteristic fingerprints of chemokine receptors that determine their complex responses to chemokines and define their migratory paths in the body with different receptors playing either nonredundant, combinatorial or overlapping roles. The interactions of individual chemokines and receptors are nonrandom and have been comprehensively characterized. According to new findings, still pending independent confirmation, the last remaining orphan chemokine, CXCL14, known to bind and allosterically modify chemokine receptors, including CXCR4, but not directly signal perse, triggers its own GPCR and GPR85. Each chemokine receptor binds either one chemokine or a defined set of them and any individual chemokine can ligate either one unique or several different receptors resulting in some overlap in specificities. However, there are multiple reasons why the apparent “promiscuity” of chemokine-receptor interactions is not a sign of chemokine redundancy and does not reflect a tautology of their signals. First, while the receptor use by different chemokines might overlap, the full spectra of receptors triggered by any particular chemokine are mostly distinct and characteristic for a chemokine, especially within the CC subfamily. Thus, individual chemokines can unmistakably be recognized, albeit in many cases not by one receptor, but by their entire system. Second, messages encoded by individual chemokines that ligate the same receptor are largely unique, because different chemokines have highly disparate binding affinities, inter act with distinct receptor moieties and consequently lead to biased signaling, i.e., they induce a dissimilar “texture” of intracellular secondary effectors, activating some and inhibiting others, ultimately resulting in unique spectra of downstream molecular and cellular responses. For example, homologous chemokines CCL17 and CCL22 signaling through their cognate receptor CCR4 leads to differential molecular and functional outcomes. CCL19 and CCL21 provide another example of differential, biased signaling through their common receptor CCR7, whereby individually or in combination they can induce variations of directed migratory cell responses, including chemotaxis, haptotaxis or chemorepulsion. Third, chemokines with an apparent overlap of their receptor specificity can behave fundamentally dissimilar due to their differential physicochemical properties, e.g., occurring primarily as soluble versus substrate-bound, as again exemplified by CCL19 and CCL21. Fourth, individual chemokines that ligate the same receptor are produced in vivo in different tissues and/or derive from different cells and/or localize in alternate tissue microenvironments, thus do not act simultaneously but induce distinct, often sequential, steps of leukocyte migratory paths. This was recently shown for two CXCR2 ligands, CXCL1 and CXCL2, which are produced in the vessel wall and by migrating neutrophils, respectively, localize in distinct microanatomical foci thus induce sequential steps of neutrophil emigration. In summary, there are no two chemokines alike and their endless possible combinations allow these structurally homologous signaling molecules to convey most diverse cellular messages acting as building blocks of a universal cell language.
The total number of unique chemokines is further increased by single nucleotide polymorphisms of genes encoding them and their several known spliced variants.Also, practically all chemokines undergo post-translational modifications of their main secreted forms with specific enzymes and protein-modifying agents inducing truncation, degradation, nitration or citrullination of chemokines. Many of such modified chemokine isoforms have altered affinity and spectrum of agonistic activities on different receptors and, in some cases, are rendered completely inactive by their processing or gain receptor antagonistic profile. Proteases prominently implicated in processing chemokines include dipeptidyl peptidase IV, also known as CD26, which cleaves two NH2-terminal amino acids of chemokines with alanine or proline at the N-terminal penultimate position, sometimes sequentially, elastase, the ADAM family, as well as matrix metalloproteases (MMPs), a family of more than 20 enzymes with important functions in matrix degradation and multifaceted roles in inflammatory leukocyte recruitment. Conversely, some chemokines including CCL14, CCL15, CCL16, and CCL23 are secreted as precursors and their receptor interactive forms are generated upon proteolytic processing by serine proteases and MMPs abundant in the inflammatory tissue environments. Also, chemokine processing by glutaminyl cyclase, the modifications to pyroglutamate of their N-terminal amino acids in CCL2 and CX3CL1, is required for protecting these chemokines from proteolysis in vivo and is required for their biological activity. Further intricacy of chemokine signaling is achieved by the propensity of chemokines to dimerize and oligomerize with chemokine monomers and dimers differentially ligating receptors and causing biased signaling, as has been shown recently for CXCL12. Moreover many, but not all, chemokines form heterodimers within and across their structural sub-family boundaries following a recently mapped pattern of nonrandom specificity. The resultant chemokine heterodimers shift the use of their receptors as compared to the individual monomeric chemokines.
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