Chitosan/siRNA nanoparticle-mediated TNF-alpha knockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model
- Authors:
-
- Howard, Kenneth Alan ;
- Paludan, Søren R ;
- Behlke, Mark A ;
- Besenbacher, Flemming ;
-
Deleuran, Bent Winding
;
Close
0000-0002-7079-1587
Department of Biomedicine - Medical Microbiology and Immunology, Department of Biomedicine, Health, Aarhus University - Kjems, Jørgen
- DOI:
- 10.1038/mt.2008.220
- Abstract:
- Secretion of tumor necrosis factor-alpha (TNF-alpha) by macrophages plays a predominant role in the development and progression of rheumatoid arthritis. We demonstrate that knockdown of TNF-alpha expression in systemic macrophages by intraperitoneal (i.p.) administration of chitosan/small interfering RNA (siRNA) nanoparticles in mice downregulates systemic and local inflammation. Chitosan nanoparticles containing an unmodified anti-TNF-alpha Dicer-substrate siRNA (DsiRNA) mediated TNF-alpha knockdown (approximately 66%) in primary peritoneal macrophages in vitro. The presence of Cy3-labeled nanoparticles within peritoneal macrophages and specific TNF-alpha knockdown (approximately 44%) with TNF-alpha siRNA after i.p. injection supports our therapeutic approach. Downregulation of TNF-alpha-induced inflammatory responses arrested joint swelling in collagen-induced arthritic (CIA) mice dosed i.p. with anti-TNF-alpha DsiRNA nanoparticles. The use of 2'-O-Me-modified DsiRNA resulted in the lowest arthritic scores and correlated with reduced type I interferon (IFN) activation in macrophages in vivo compared with unmodified DsiRNA. Histological analysis of joints revealed minimal cartilage destruction and inflammatory cell infiltration in anti-TNF-alpha-treated mice. The onset of arthritis could be delayed using a prophylactic dosing regime. This work demonstrates nanoparticle-mediated TNF-alpha knockdown in peritoneal macrophages as a method to reduce both local and systemic inflammation, thereby presenting a novel strategy for arthritis treatment.
- Type:
- Journal article
- Language:
- English
- Published in:
- Molecular Therapy, 2008, Vol 17, Issue 1, p. 162-168
- Keywords:
- Animals; Arthritis, Experimental; Chitosan; Collagen Type II; Female; Inflammation; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Nanoparticles; RNA, Small Interfering; Tumor Necrosis Factor-alpha
- Main Research Area:
- Science/technology
- Publication Status:
- Published
- Review type:
- Peer Review
- Submission year:
- 2008
- Scientific Level:
- Scientific
- ID:
- 113392352
