Mannan-Binding Lectin-Associated Serine Protease 1/3 Cleavage of Pro-Factor D into Factor D In Vivo and Attenuation of Collagen Antibody-Induced Arthritis through Their Targeted Inhibition by RNA Interference-Mediated Gene Silencing
| Autor: | Robert I. Scheinman, Steffen Thiel, Minoru Takahashi, Nirmal K. Banda, Marilyne Coulombe, Teizo Fujita, Hideharu Sekine, V. Michael Holers, Sumitra Acharya, Gaurav Mehta |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Small interfering RNA Immunology Arthritis Mannose-Binding Lectin Article Arthritis Rheumatoid 03 medical and health sciences Mice 0302 clinical medicine medicine Immunology and Allergy Gene silencing Animals Humans RNA Small Interfering Mannan-binding lectin Mice Knockout biology Complement Pathway Mannose-Binding Lectin medicine.disease Molecular biology Arthritis Experimental Complement system Mice Inbred C57BL 030104 developmental biology Lectin pathway Mannose-Binding Protein-Associated Serine Proteases Proteolysis biology.protein Alternative complement pathway Factor D Complement Factor D RNA Interference 030215 immunology |
| Zdroj: | Banda, N K, Acharya, S, Scheinman, R I, Mehta, G, Coulombe, M, Takahashi, M, Sekine, H, Thiel, S, Fujita, T & Holers, V M 2016, ' Mannan-Binding Lectin-Associated Serine Protease 1/3 Cleavage of Pro-Factor D into Factor D In Vivo and Attenuation of Collagen Antibody-Induced Arthritis through Their Targeted Inhibition by RNA Interference-Mediated Gene Silencing ', Journal of Immunology, vol. 197, no. 9, pp. 3680-3694 . https://doi.org/10.4049/jimmunol.1600719 |
| Popis: | The complement system is proposed to play an important role in the pathogenesis of rheumatoid arthritis (RA). The complement system mannan-binding lectin–associated serine proteases (MASP)-1/3 cleave pro–factor D (proDf; inactive) into Df (active), but it is unknown where this cleavage occurs and whether inhibition of MASP-1/3 is a relevant therapeutic strategy for RA. In the present study, we show that the cleavage of proDf into Df by MASP-1/3 can occur in the circulation and that inhibition of MASP-1/3 by gene silencing is sufficient to ameliorate collagen Ab–induced arthritis in mice. Specifically, to examine the cleavage of proDf into Df, MASP-1/3–producing Df−/− liver tissue (donor) was transplanted under the kidney capsule of MASP-1/3−/− (recipient) mice. Five weeks after the liver transplantation, cleaved Df was present in the circulation of MASP-1/3−/− mice. To determine the individual effects of MASP-1/3 and Df gene silencing on collagen Ab–induced arthritis, mice were injected with scrambled, MASP-1/3–targeted, or Df-targeted small interfering RNAs (siRNAs). The mRNA levels for MASP-1 and -3 decreased in the liver to 62 and 58%, respectively, in mice injected with MASP-1/3 siRNAs, and Df mRNA decreased to 53% in the adipose tissue of mice injected with Df siRNAs; additionally, circulating MASP-1/3 and Df protein levels were decreased. In mice injected with both siRNAs the clinical disease activity, histopathologic injury scores, C3 deposition, and synovial macrophage/neutrophil infiltration were significantly decreased. Thus, MASP-1/3 represent a new therapeutic target for the treatment of RA, likely through both direct effects on the lectin pathway and indirectly through the alternative pathway. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|