Dataset Information

Elucidating the Molecular Interactions of Chemokine CCL2 Orthologs with Flavonoid Baicalin.

ABSTRACT: An integrated and controlled migration of leukocytes is necessary for the legitimate functioning and maintenance of the immune system. Chemokines and their receptors play a decisive role in regulating the leukocyte migration to the site of inflammation, a phenomena often referred to as chemotaxis. Chemokines and their receptors have become significant targets for therapeutic intervention considering their potential to regulate the immune system. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a preeminent member of CC chemokine family that facilitates crucial roles by orchestrating the recruitment of monocytes into inflamed tissues. Baicalin (BA), a major bioactive flavonoid, has been reported to attenuate chemokine-regulated leukocyte trafficking. However, no molecular details pertaining to its direct binding to chemokine(s)/receptor(s) are available till date. In the current study, using an array of monomers/dimers of human and murine CCL2 orthologs (hCCL2/mCCL2), we have shown that BA binds to the CCL2 protein specifically with nanomolar affinity (K d = 270 ± 20 nM). NMR-based studies established that BA binds CCL2 in a specific pocket involving the N-terminal, ?1- and ?3-sheets. Docking studies suggested that the residues T16, N17, R18, I20, R24, K49, E50, I51, and C52 are majorly involved in complex formation through a combination of H-bonds and hydrophobic interactions. As the residues R18, R24, and K49 of hCCL2 are crucial determinants of monocyte trafficking through receptor/glycosaminoglycans (GAG) binding in CCL2 human/murine orthologs, we propose that baicalin engaging these residues in complex formation will result in attenuation of CCL2 binding to the receptor/GAGs, thus inhibiting the chemokine-regulated leukocyte trafficking.

SUBMITTER: Joshi N

PROVIDER: S-EPMC7482410 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Elucidating the Molecular Interactions of Chemokine CCL2 Orthologs with Flavonoid Baicalin.

Joshi Nidhi N Kumar Dinesh D Poluri Krishna Mohan KM

ACS omega 20200824 35

An integrated and controlled migration of leukocytes is necessary for the legitimate functioning and maintenance of the immune system. Chemokines and their receptors play a decisive role in regulating the leukocyte migration to the site of inflammation, a phenomena often referred to as chemotaxis. Chemokines and their receptors have become significant targets for therapeutic intervention considering their potential to regulate the immune system. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is ...[more]

PMID: 32923824

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Project description:Microglia and macrophages are recruited to sites of retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to retinal telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2(-/-)/Crb1(Rd8/RD8), Cx3cr1(-/-)/Crb1(Rd8/RD8) and CCl2(-/-)/Cx3cr1(-/-)/Crb1(Rd8/RD8) mice, we observed a differential modulation of the retinal phenotype by genetic background and both chemokine signalling pathways. These findings indicate that CCDKO mice are not a model of AMD, but a model for an inherited retinal degeneration that is differentially modulated by Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling.

Dataset Information

Elucidating the Molecular Interactions of Chemokine CCL2 Orthologs with Flavonoid Baicalin.

Publications

Elucidating the Molecular Interactions of Chemokine CCL2 Orthologs with Flavonoid Baicalin.

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