Interferon-gamma regulates inflammatory cell death by targeting necroptosis in experimental autoimmune arthritis

Abstract

Interferon γ (IFN-γ) induces an inflammatory response and apoptotic cell death. Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with increased levels of inflammatory mediators, including tumour necrosis factor α (TNF-α) and T helper (Th) 17 cells, and downregulation of apoptosis of inflammatory cells. We hypothesized that IFN-γ would reduce inflammatory cell death in vitro and that loss of IFN-γ would aggravate inflammation in vivo. IFN-γ downregulated necroptosis and the expression of cellular FLICE-like inhibitory protein (cFLIPL) and mixed lineage kinase domain-like (MLKL). However, loss of IFN-γ promoted the production of cFLIPL and MLKL, and necroptosis. IFN-γ deficiency increased Th17 cell number and upregulated the expression of IL-17 and TNF-α. Expression of MLKL, receptor interacting protein kinase (RIPK)1, and RIPK3 was increased in the joints of mice with collagen-induced arthritis (CIA). Compared with wild-type mice with CIA, IFN-γ−/− CIA mice showed exacerbation of cartilage damage and joint inflammation, and acceleration of MLKL, RIPK1, and RIPK3 production in the joints. IFN-γ deficiency induced the activation of signal transducer and activator of transcription 3. These results suggest that IFN-γ regulates inflammatory cell death and may have potential for use in the treatment of RA.

Serial Monitoring of Immune Markers Being Represented Regulatory T Cell/T Helper 17 Cell Ratio: Indicating Tolerance for Tapering Immunosuppression after Liver Transplantation

“…It has been suggested that activation of CD8 +EM T cells through the T-cell antigen receptor and the costimulatory receptor CD28 induces rapid IFN-γ expression ( 27 ). Currently, IFN-γ can regulate necroptosis and loss of IFN-γ aggravated experimental autoimmune disorder through upregulation of Th17 cells differentiation ( 28 ). Since, necroptosis has been observed in liver-related injury and disease indicating that necroptosis can be a target of the pathogenesis of several liver diseases ( 29 , 30 ), induction of IFN-γ level can improve inflammatory response.…”

Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

“…Rheumatoid arthritis (RA) is one of the most common chronic inflammatory diseases, which is characterized by joint inflammation and osteoclastogenesis. The key regulators of necroptosis, RIPK1, RIPK3 and MLKL were potently increased in the synovium of a collagen-induced arthritis mouse model [83], indicating that necroptosis might be involved in the pathogenesis of RA. RIPK1 inhibitor Nec-1 significantly decreased the expression of these key regulators and suppressed the expression of IL-17, IL-1β, IL-6 and TNFα in the mouse model [84].…”

Necroptosis in the Pathophysiology of Disease

“…108,109 Alternatively, IFN-g suppresses the inflammatory response and has been found to be protective in autoimmune disorders. 110 Lee et al 55 investigated whether IFN-g had protective effects in autoimmune arthritis by regulating necroptosis. They found that IFN-g downregulated necroptosis and the expression of MLKL, whereas the loss of IFN-g increased the expression of MLKL and promoted necroptosis.…”