Modulation of Macrophage Functional Polarity towards Anti-Inflammatory Phenotype with Plasmid DNA Delivery in CD44 Targeting Hyaluronic Acid Nanoparticles

• Published in: Scientific reports 2015-11, Vol.5 (1), p.16632, Article 16632
• Main Authors: Tran, Thanh-Huyen, Rastogi, Ruchir, Shelke, Juili, Amiji, Mansoor M.
• Format: Article
• Language: English
• Subjects: 13/21; 14/19; 42/41; 42/44; 59/5; 631/61/2300/1514; 692/308/153; 96/1; 96/31; Animals; CD163 antigen; CD44 antigen; Cytokines; Cytokines - metabolism; Deoxyribonucleic acid; DNA; Gene Expression; Genotype & phenotype; Humanities and Social Sciences; Hyaluronan Receptors - metabolism; Hyaluronic acid; Hyaluronic Acid - chemistry; IL-1β; Inflammation Mediators - metabolism; Inflammatory diseases; Interleukin 1; Interleukin 10; Interleukin 4; Interleukin-10 - genetics; Interleukin-4 - genetics; Lipopolysaccharides; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; Nanoparticles; Nanoparticles - chemistry; Nitric-oxide synthase; Peritoneal fluid; Peritoneum; Phenotype; Phenotypes; Plasmids - genetics; Polarity; Polyethyleneimine; Rodents; Science; Transfection; Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep16632

The purpose of this study was to modulate macrophage polarity from the pro-inflammatory M1 to anti-inflammatory M2 phenotype using plasmid DNA (pDNA) expressing interleukin-4 (IL4) or interleukin-10 (IL10)-encapsulated in hyaluronic acid-poly(ethyleneimine) (HA-PEI) nanoparticles (NPs). The HA-PEI/pDNA NPs with spherical shape, average size of 186 nm were efficiently internalized by J774A.1 macrophages. Transfection of HA-PEI/pDNA-IL4 and HA-PEI/pDNA-IL10 NPs increased IL4 and IL10 gene expression in J774 macrophages which could re-program the macrophages from M1 to M2 phenotype as evidenced by a significant increase in the Arg/iNOS level and upregulation of CD206 and CD163 compared to untreated macrophages. Following intraperitoneal (IP) injection to C57BL/6 mice, HA-PEI NPs effectively targeted peritoneal macrophages over-expressing CD44 receptor. In an in vivo model of stimulated peritoneal macrophages, IP administration of HA-PEI/pDNA-IL4 and HA-PEI/pDNA-IL10 to C57BL/6 mice significantly increased the Arg/iNOS ratio and CD163 expression in the cells. Furthermore, HA-PEI/pDNA-IL10 NPs significantly increased peritoneal and serum IL10 levels which effectively suppressed LPS-induced inflammation by reducing level of TNF-α and IL-1β in peritoneal macrophages and in the peritoneal fluid. The results demonstrated that pDNA-IL10-encapsulate HA-PEI NPs skewed macrophage functional polarity from M1 toward an anti-inflammatory M2 phenotype which may be a promising platform for the treatment of inflammatory diseases.