ABSTRACT
The defective eradication of invading pathogens is a major cause of death in sepsis. As professional phagocytic cells, macrophages actively engulf/kill microorganisms and play essential roles in innate immune response against pathogens. Growth differentiation factor 3 (GDF3) was previously implicated as an important modulator of inflammatory response upon acute sterile injury. In this study, administration of recombinant GDF3 protein (rGDF3) either before or after CLP surgery remarkably improved mouse survival, along with significant reductions in bacterial load, plasma pro-inflammatory cytokine levels, and organ damage. Notably, our in vitro experiments revealed that rGDF3 treatment substantially promoted macrophage phagocytosis and intracellular killing of bacteria in a dose-dependent manner. Mechanistically, RNA-seq analysis results showed that CD5L, known to be regulated by liver X receptor α (LXRα), was the most significantly upregulated gene in rGDF3-treated macrophages. Furthermore, we observed that rGDF3 could promote LXRα nuclear translocation and thereby, augmented phagocytosis activity in macrophages, which was similar as LXRα agonist GW3965 did. By contrast, pre-treating macrophages with LXRα antagonist GSK2033 abolished beneficial effects of rGDF3 in macrophages. In addition, rGDF3 treatment failed to enhance bacteria uptake and killing in LXRα-knockout (KO) macrophages. Taken together, these results uncover that GDF3 may represent a novel mediator for controlling bacterial infection.
Subject(s)
Growth Differentiation Factor 3/pharmacology , Liver X Receptors/immunology , Macrophages/drug effects , Phagocytosis/drug effects , Recombinant Proteins/pharmacology , Sepsis/prevention & control , Animals , Benzoates/pharmacology , Benzylamines/pharmacology , Cells, Cultured , Cytokines/immunology , Cytokines/metabolism , Gene Expression/drug effects , Gene Expression/immunology , Gene Expression Profiling/methods , Growth Differentiation Factor 3/administration & dosage , Growth Differentiation Factor 3/genetics , Liver/drug effects , Liver/immunology , Liver/microbiology , Liver X Receptors/metabolism , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Phagocytosis/immunology , RAW 264.7 Cells , Recombinant Proteins/administration & dosage , Reverse Transcriptase Polymerase Chain Reaction , Sepsis/immunology , Sepsis/microbiologyABSTRACT
Tissue regeneration is a highly coordinated process with sequential events including immune cell infiltration, clearance of damaged tissues, and immune-supported regrowth of the tissue. Aging has a well-documented negative impact on this process globally; however, whether changes in immune cells per se are contributing to the decline in the body's ability to regenerate tissues with aging is not clearly understood. Here, we set out to characterize the dynamics of macrophage infiltration and their functional contribution to muscle regeneration by comparing young and aged animals upon acute sterile injury. Injured muscle of old mice showed markedly elevated number of macrophages, with a predominance for Ly6Chigh pro-inflammatory macrophages and a lower ratio of the Ly6Clow repair macrophages. Of interest, a recently identified repair macrophage-derived cytokine, growth differentiation factor 3 (GDF3), was markedly downregulated in injured muscle of old relative to young mice. Supplementation of recombinant GDF3 in aged mice ameliorated the inefficient regenerative response. Together, these results uncover a deficiency in the quantity and quality of infiltrating macrophages during aging and suggest that in vivo administration of GDF3 could be an effective therapeutic approach.
Subject(s)
Aging/pathology , Growth Differentiation Factor 3/administration & dosage , Growth Differentiation Factor 3/pharmacology , Muscle, Skeletal/injuries , Muscle, Skeletal/physiopathology , Regeneration/drug effects , Acute Disease , Aging/drug effects , Animals , Cell Differentiation/drug effects , Kinetics , Male , Mice , Muscle, Skeletal/drug effects , Myoblasts/drug effects , Myoblasts/metabolism , Myoblasts/pathology , PhenotypeABSTRACT
The authors synthesised porous GdF3:Er3+,Yb3+-COOH core-shell structured bi-functional nanoparticles through a one-step hydrothermal route during which ethylene diamine tetraacetic acid) was bound to the surface of the nanoparticles. It has high up-conversion emission intensity for monitoring the drug release process and magnetisation saturation value (10.2â emu/g) for drug targeting under foreign magnetic fields. Moreover, porous GdF3:Er3+,Yb3+ as drug carriers with a high drug-loading efficiency. cis-Dichlorodiammineplatinum(II) (cisplatin, CDDP)-loaded GdF3:Er3+,Yb3+ nanoparticles (GdF3:Er3+,Yb3+-CDDP) were characterised by the Fourier transform infrared spectra, and CDDP was loaded in the form of electrostatic interaction and hydrogen bonds. Compared with CDDP alone, GdF3:Er3+,Yb3+-CDDP nanoparticles increase concentration of CDDP in the target site and enhance its anticancer efficiency. Therefore, the as-prepared GdF3:Er3+,Yb3+-COOH nanoparticles allow simultaneous targeted drug delivery and monitoring as promising anti-cancer theranostic agents.
