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Immunoregulation of macrophages by dynamic ligand presentation via ligand-cation coordination.

ABSTRACT: Macrophages regulate host responses to implants through their dynamic adhesion, release, and activation. Herein, we employ bisphosphonate (BP)-coated gold nanoparticle template (BNP) to direct the swift and convertible formation of Mg²⁺-functional Mg²⁺-BP nanoparticle (NP) on the BP-AuNP surface via reversible Mg²⁺-BP coordination, thus producing (Mg²⁺-BP)-Au dimer (MgBNP). Ethylenediaminetetraacetic acid-based Mg²⁺ chelation facilitates the dissolution of Mg²⁺-BP NP, thus enabling the reversion of the MgBNP to the BNP. This convertible nanoassembly incorporating cell-adhesive Mg²⁺ moieties directs reversible attachment and detachment of macrophages by BP and EDTA, without physical scraping or trypsin that could damage cells. The swift formation of RGD ligand- and Mg²⁺-bifunctional RGD-Mg²⁺-BP NP that yields (RGD-Mg²⁺-BP)-Au dimer (RGDBNP) further stimulates the adhesion and pro-regenerative M2-type polarization of macrophages, both in vitro and in vivo, including rho-associated protein kinase. This swift and non-toxic dimer formation can include diverse bio-functional moieties to regulate host responses to implants.

SUBMITTER: Kang H

PROVIDER: S-EPMC6461616 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Immunoregulation of macrophages by dynamic ligand presentation via ligand-cation coordination.

Kang Heemin H Yang Boguang B Zhang Kunyu K Pan Qi Q Yuan Weihao W Li Gang G Bian Liming L

Nature communications 20190412 1

Macrophages regulate host responses to implants through their dynamic adhesion, release, and activation. Herein, we employ bisphosphonate (BP)-coated gold nanoparticle template (BNP) to direct the swift and convertible formation of Mg2+-functional Mg2+-BP nanoparticle (NP) on the BP-AuNP surface via reversible Mg2+-BP coordination, thus producing (Mg2+-BP)-Au dimer (MgBNP). Ethylenediaminetetraacetic acid-based Mg2+ chelation facilitates the ...[more]

PMID: 30979900

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Project description:BackgroundRestenosis is one of the worst side effects of percutaneous coronary intervention (PCI) due to neointima formation resulting from the excessive proliferation and migration of vascular smooth muscle cells (VSMCs) and continuous inflammation. Biodegradable Mg-based alloy is a promising candidate material because of its good mechanical properties and biocompatibility, and biodegradation of cardiovascular stents. Although studies have shown reduced neointima formation after Mg-based CVS implantation in vivo, these findings were inconsistent with in vitro studies, demonstrating magnesium-mediated promotion of the proliferation and migration of VSMCs. Given the vital role of activated macrophage-driven inflammation in neointima formation, along with the well-demonstrated crosstalk between macrophages and VSMCs, we investigated the interactions of a biodegradable Mg-Nd-Zn-Zr alloy (denoted JDBM), which is especially important for cardiovascular stents, with VSMCs via macrophages.MethodsJDBM extracts and MgCl2 solutions were prepared to study their effect on macrophages. To study the effects of the JDBM extracts and MgCl2 solutions on the function of VSMCs via immunoregulation of macrophages, conditioned media (CM) obtained from macrophages was used to establish a VSMC-macrophage indirect coculture system.ResultsOur results showed that both JDBM extracts and MgCl2 solutions significantly attenuated the inflammatory response stimulated by lipopolysaccharide (LPS)-activated macrophages and converted macrophages into M2-type cells. In addition, JDBM extracts and MgCl2 solutions significantly decreased the expression of genes related to VSMC phenotypic switching, migration, and proliferation in macrophages. Furthermore, the proliferation, migration, and proinflammatory phenotypic switching of VSMCs were significantly inhibited when the cells were incubated with CMs from macrophages treated with LPS + extracts or LPS + MgCl2 solutions.ConclusionsTaken together, our results suggested that the magnesium in the JDBM extract could affect the functions of VSMCs through macrophage-mediated immunoregulation, inhibiting smooth muscle hyperproliferation to suppress restenosis after implantation of a biodegradable Mg-based stent.

Project description:BackgroundAlternative strategies are required to control the southern cattle tick, Rhipicephalus microplus, due to evolving resistance to commercially available acaricides. This invasive ectoparasite is a vector of economically important diseases of cattle such as bovine babesiosis and anaplasmosis. An understanding of the biological intricacies underlying vector-host-pathogen interactions is required to innovate sustainable tick management strategies that can ultimately mitigate the impact of animal and zoonotic tick-borne diseases. Tick saliva contains molecules evolved to impair host innate and adaptive immune responses, which facilitates blood feeding and pathogen transmission. Antigen presenting cells are central to the development of robust T cell responses including Th1 and Th2 determination. In this study we examined changes in co-stimulatory molecule expression and cytokine response of bovine macrophages exposed to salivary gland extracts (SGE) obtained from 2-3 day fed, pathogen-free adult R. microplus.MethodsPeripheral blood-derived macrophages were treated for 1 hr with 1, 5, or 10 μg/mL of SGE followed by 1, 6, 24 hr of 1 μg/mL of lipopolysaccharide (LPS). Real-time PCR and cytokine ELISA were used to measure changes in co-stimulatory molecule expression and cytokine response.ResultsChanges were observed in co-stimulatory molecule expression of bovine macrophages in response to R. microplus SGE exposure. After 6 hrs, CD86, but not CD80, was preferentially up-regulated on bovine macrophages when treated with 1 μg/ml SGE and then LPS, but not SGE alone. At 24 hrs CD80, CD86, and CD69 expression was increased with LPS, but was inhibited by the addition of SGE. SGE also inhibited LPS induced upregulation of TNFα, IFNγ and IL-12 cytokines, but did not alter IL-4 or CD40 mRNA expression.ConclusionsMolecules from the salivary glands of adult R. microplus showed bimodal concentration-, and time-dependent effects on differential up-regulation of CD86 in bovine macrophages activated by the TLR4-ligand, LPS. Up regulation of proinflammatory cytokines and IL-12, a Th1 promoting cytokine, were inhibited in a dose-dependent manner. The co-stimulatory molecules CD80, as well as the cell activation marker, CD69, were also suppressed in macrophages exposed to SGE. Continued investigation of the immunomodulatory factors will provide the knowledge base to research and develop therapeutic or prophylactic interventions targeting R. microplus-cattle interactions at the blood-feeding interface.

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Immunoregulation of macrophages by dynamic ligand presentation via ligand-cation coordination.

Publications

Immunoregulation of macrophages by dynamic ligand presentation via ligand-cation coordination.

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