RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis

• Published in: Journal of translational medicine 2019-03, Vol.17 (1), p.84-84, Article 84
• Main Authors: Jhun, Jooyeon, Lee, Seung Hoon, Kim, Se-Young, Ryu, Jaeyoon, Kwon, Ji Ye, Na, Hyun Sik, Jung, KyoungAh, Moon, Su-Jin, Cho, Mi-La, Min, Jun-Ki
• Format: Article
• Language: English
• Subjects: Animals; Ankle; Apoptosis; Arthritis; Arthritis, Experimental - enzymology; Arthritis, Experimental - pathology; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - pathology; Care and treatment; Cell death; Chemical compounds; Collagen; Cytokines; Cytokines - metabolism; Disease; Government agencies; Helper cells; Imidazoles - pharmacology; Imidazoles - therapeutic use; Indoles - pharmacology; Indoles - therapeutic use; Inflammation; Inflammation - pathology; Inflammation Mediators - metabolism; Inflammatory diseases; Inhibition; Kinases; Laboratory animals; Lymphocytes T; Male; MAP kinase; Mice, Inbred DBA; Necroptosis; Necrosis; Necrostatin-1s; Osteoclastogenesis; Osteoclasts (Biology); Osteogenesis - drug effects; Protein kinase; Protein kinases; Proteins; Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Rheumatoid arthritis; T-Lymphocytes - drug effects; Threonine; Tumor necrosis factor-TNF
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-019-1809-3

Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by upregulation of inflammatory cell death and osteoclastogenesis. Necrostatin (NST)-1s is a chemical inhibitor of receptor-interacting serine/threonine-protein kinase (RIPK)1, which plays a role in necroptosis. We investigated whether NST-1s decreases inflammatory cell death and inflammatory responses in a mouse model of collagen-induced arthritis (CIA). NST-1s decreased the progression of CIA and the synovial expression of proinflammatory cytokines. Moreover, NST-1s treatment decreased the expression of necroptosis mediators such as RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL). In addition, NST-1s decreased osteoclastogenesis in vitro and in vivo. NST-1s downregulated T helper (Th)1 and Th17 cell expression, but promoted Th2 and regulatory T (Treg) cell expression in CIA mice. These results suggest that NST-1s attenuates CIA progression via the inhibition of osteoclastogenesis and might be a potential therapeutic agent for RA therapy.