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Tag7-Mts1 Complex Induces Lymphocytes Migration via CCR5 and CXCR3 Receptors.

ABSTRACT: The discovery of new chemokines that induce the migration of lymphocytes to the infection site is important for the targeted search for therapeutic agents in immunotherapy. We recently showed that Tag7 (PGLYRP1), an innate immunity protein, forms a stable complex with the Ca2+ -binding protein Mts1 (S100A4), which is able to induce lymphocyte movement, although the individual Tag7 and Mts1 do not have this activity. The purpose of this study is to identify receptors that induce the migration of lymphocytes along the concentration gradient of the Tag7-Mts1 complex, and the components of this complex capable of interacting with these receptors. The study investigated the migration of human PBMC under the action of the Tag7-Mts1complex. PBMC of healthy donors were isolated using a standard Ficoll-Hypaque gradient centrifugation procedure. It has been established that the movement of PBMC along the concentration gradient of the Tag7-Mts1 complex is induced by the classical chemotactic receptors CCR5 and CXCR3. It has been shown that only Mts1 is able to bind to the extracellular domain of CCR5, however, this binding is not enough to induce cell movement. A comparative analysis of the primary and 3D structures of the three proteins revealed the homology of the amino acid sequence fragments of the Tag7-Mts1 protein complex with different sites of the CCR5 receptor ligand - MIP1? protein. In conclusion, it should be noted that the Tag7-Mts1 complex can be considered as a new ligand of the classical chemotactic receptors CCR5 and CXCR3.

SUBMITTER: Sharapova TN

PROVIDER: S-EPMC6351033 | biostudies-literature | 2018 Oct-Dec

REPOSITORIES: biostudies-literature

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Tag7-Mts1 Complex Induces Lymphocytes Migration via CCR5 and CXCR3 Receptors.

Sharapova T N TN Romanova E A EA Sashchenko L P LP Yashin D V DV

Acta naturae 20181001 4

The discovery of new chemokines that induce the migration of lymphocytes to the infection site is important for the targeted search for therapeutic agents in immunotherapy. We recently showed that Tag7 (PGLYRP1), an innate immunity protein, forms a stable complex with the Ca<sup>2+</sup> -binding protein Mts1 (S100A4), which is able to induce lymphocyte movement, although the individual Tag7 and Mts1 do not have this activity. The purpose of this study is to identify receptors that induce the mi ...[more]

PMID: 30713770

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Project description:BACKGROUND:Mesenchymal stem cells (MSCs) are known to home to injured and inflamed regions via the bloodstream to assist in tissue regeneration in response to signals of cellular damage. However, the factors and mechanisms that affect their transendothelial migration are still unclear. In this study, the mechanisms involved in interleukin-1? (IL-1?) enhancing the transendothelial migration of MSCs were investigated. METHODS:Immunofluorescence staining and Western blotting were used to observe IL-1?-induced CXC chemokine receptor 3 (CXCR3) expression on MSCs. Quantitative real-time PCR and ELISA were used to demonstrate IL-1? upregulated both chemokine (C-X-C motif) ligand 9 (CXCL9) mRNA and CXCL9 ligand secretion in human umbilical vein endothelial cells (HUVECs). Monolayer co-cultivation, agarose drop chemotaxis, and transwell assay were conducted to investigate the chemotaxis invasion and transendothelial migration ability of IL-1?-induced MSCs in response to CXCL9. RESULTS:In this study, our immunofluorescence staining showed that IL-1? induces CXCR3 expression on MSCs. This result was confirmed by Western blotting. Following pretreatment with protein synthesis inhibitor cycloheximide, we found that IL-1? induced CXCR3 on the surface of MSCs via protein synthesis pathway. Quantitative real-time PCR and ELISA validated that IL-1? upregulated both CXCL9 mRNA and CXCL9 ligand secretion in HUVECs. In response to CXCL9, chemotaxis invasion and transendothelial migration ability were increased in IL-1?-stimulated MSCs. In addition, we pretreated MSCs with CXCR3 antagonist AMG-487 and p38 MAPK inhibitor SB203580 to confirm CXCR3-CXCL9 interaction and the role of CXCR3 in IL-1?-induced chemotaxis invasion and transendothelial migration. CONCLUSION:We found that IL-1? induces the expression of CXCR3 through p38 MAPK signaling and that IL-1? also enhances CXCL9 ligand secretion in HUVECs. These results indicated that IL-1? promotes the transendothelial migration of MSCs through CXCR3-CXCL9 axis. The implication of the finding could enhance the efficacy of MSCs homing to target sites.

Project description:Naive T lymphocytes exhibit extensive antigen-independent recirculation between blood and lymph nodes, where they may encounter dendritic cells carrying cognate antigen. We examine how long different T cells may spend in an individual lymph node by examining data from long term cannulation of blood and efferent lymphatics of a single lymph node in the sheep. We determine empirically the distribution of transit times of migrating T cells by applying the Least Absolute Shrinkage & Selection Operator (LASSO) or regularised S-LASSO to fit experimental data describing the proportion of labelled infused cells in blood and efferent lymphatics over time. The optimal inferred solution reveals a distribution with high variance and strong skew. The mode transit time is typically between 10 and 20 hours, but a significant number of cells spend more than 70 hours before exiting. We complement the empirical machine learning based approach by modelling lymphocyte passage through the lymph node insilico. On the basis of previous two photon analysis of lymphocyte movement, we optimised distributions which describe the transit times (first passage times) of discrete one dimensional and continuous (Brownian) three dimensional random walks with drift. The optimal fit is obtained when drift is small, i.e. the ratio of probabilities of migrating forward and backward within the node is close to one. These distributions are qualitatively similar to the inferred empirical distribution, with high variance and strong skew. In contrast, an optimised normal distribution of transit times (symmetrical around mean) fitted the data poorly. The results demonstrate that the rapid recirculation of lymphocytes observed at a macro level is compatible with predominantly randomised movement within lymph nodes, and significant probabilities of long transit times. We discuss how this pattern of migration may contribute to facilitating interactions between low frequency T cells and antigen presenting cells carrying cognate antigen.

Dataset Information

Tag7-Mts1 Complex Induces Lymphocytes Migration via CCR5 and CXCR3 Receptors.

Publications

Tag7-Mts1 Complex Induces Lymphocytes Migration via CCR5 and CXCR3 Receptors.

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