ABSTRACT
Biomaterials have the potential to be utilized as immunostimulatory or immunosuppressive delivery agents for biologics. It is hypothesized that this is directed by the ability of a biomaterial to drive dendritic cells (DC) in situ toward an immunostimulatory or an immunosuppressive phenotype, respectively. However, the specific pattern recognition receptors (PRRs) that DCs use to recognize and respond to biomaterials are unknown. From among the many receptors that DCs use to recognize and respond to foreign entities, herein the focus is on integrins. A biomaterial that induces DC maturation, namely poly(lactic-co-glycolic) acid (PLGA), supported increased human monocyte-derived DC adhesion and up-regulation of integrin receptor gene expression, measured via RT-PCR, as compared to culture on tissue culture polystyrene (TCPS). This was not observed for a biomaterial that does not support DC maturation. Through antibody-blocking techniques, the adhesion to both TCPS and PLGA was found to be ß(2) integrin dependent and ß(1) independent. Significantly, inhibiting ß(2)-mediated adhesion to biomaterials via blocking antibodies also lowered the level of maturation of DCs (CD86 expression). ß(2) integrins (but not ß(1)) were found localized in biomaterial-adherent DC podosomes and also were found in direct contact with the PLGA surface. Therefore, it appeared that ß(2) integrin-mediated adhesion is involved in determining the state of DC maturation on the PLGA surface. DC adhesion to biomaterials may be engaged or avoided to manipulate an immune response to biological component delivered with a biomaterial carrier.
Subject(s)
Biocompatible Materials/pharmacology , Dendritic Cells/cytology , Dendritic Cells/metabolism , Integrins/metabolism , Biocompatible Materials/chemistry , CD18 Antigens/genetics , CD18 Antigens/metabolism , Cell Adhesion/drug effects , Cell Adhesion/genetics , Cells, Cultured , Dendritic Cells/drug effects , Fluorescent Antibody Technique , Humans , Integrin beta1/genetics , Integrin beta1/metabolism , Lactic Acid/chemistry , Lactic Acid/pharmacology , Polyglycolic Acid/chemistry , Polyglycolic Acid/pharmacology , Polylactic Acid-Polyglycolic Acid Copolymer , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
The host response to a biomaterial is characterized by both acute recruitment and attachment of cells as well as chronic encapsulating tissue reaction. The implantation procedure induces production of damage-associated molecular patterns (DAMPs) which may contribute to host recognition of the material. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that bind not only pathogen-associated molecular patterns (PAMPs) but also DAMPs. We sought to investigate whether TLR4/DAMP interactions were involved in the acute and chronic inflammatory response to an implanted biomaterial. When PET discs were implanted intraperitoneally for 16h, no differences were found in the number of leukocytes recruited between TLR4(+) (C57BL/10J) and TLR4(-) (C57BL/10ScNJ) mice. However, a significant shift in the leukocyte profile on the biomaterial surface was observed for TLR4(-) mice. While the total number of adherent cells was the same in both strains, TLR4(+) mice had a profile with equivalent neutrophil and monocyte/macrophage presence on the material surface, and TLR4(-) mice had a profile of predominantly neutrophils with fewer monocyte/macrophages. When implants were placed subcutaneously for 2 weeks, the fibrous capsule thicknesses were not different between TLR4(+) and TLR4(-) mouse strains. These findings illustrate that TLR4 may play a role in the initial recognition of a biomaterial by directing the adhesive cellular profile.
