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

ABSTRACT: Interferon ? (IFN-?) 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 ? (TNF-?) and T helper (Th) 17 cells, and downregulation of apoptosis of inflammatory cells. We hypothesized that IFN-? would reduce inflammatory cell death in vitro and that loss of IFN-? would aggravate inflammation in vivo. IFN-? downregulated necroptosis and the expression of cellular FLICE-like inhibitory protein (cFLIPL) and mixed lineage kinase domain-like (MLKL). However, loss of IFN-? promoted the production of cFLIPL and MLKL, and necroptosis. IFN-? deficiency increased Th17 cell number and upregulated the expression of IL-17 and TNF-?. 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-?-/- CIA mice showed exacerbation of cartilage damage and joint inflammation, and acceleration of MLKL, RIPK1, and RIPK3 production in the joints. IFN-? deficiency induced the activation of signal transducer and activator of transcription 3. These results suggest that IFN-? regulates inflammatory cell death and may have potential for use in the treatment of RA.

SUBMITTER: Lee SH

PROVIDER: S-EPMC5579272 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Lee Seung Hoon SH Kwon Ji Ye JY Kim Se-Young SY Jung KyoungAh K Cho Mi-La ML

Scientific reports 20170831 1

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 ...[more]

PMID: 28860618

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Project description:Compelling evidence has shown that interferon (IFN)-γ has dual effects in multiple sclerosis and in its animal model of experimental autoimmune encephalomyelitis (EAE), with results supporting both a pathogenic and beneficial function. However, the mechanisms whereby IFN-γ may promote neuroprotection in EAE and its effects on central nervous system (CNS)-resident cells have remained an enigma for more than 30 years. In this study, the impact of IFN-γ at the peak of EAE, its effects on CNS infiltrating myeloid cells (MC) and microglia (MG), and the underlying cellular and molecular mechanisms were investigated. IFN-γ administration resulted in disease amelioration and attenuation of neuroinflammation associated with significantly lower frequencies of CNS CD11b+ myeloid cells and less infiltration of inflammatory cells and demyelination. A significant reduction in activated MG and enhanced resting MG was determined by flow cytometry and immunohistrochemistry. Primary MC/MG cultures obtained from spinal cord of IFN-γ-treated EAE mice that were ex vivo re-stimulated with a low dose (1 ng/ml) of IFN-γ and neuroantigen promoted a significantly higher induction of CD4+ regulatory T (Treg) cells associated with increased transforming growth factor (TGF)-β secretion. Additionally, IFN-γ-treated primary MC/MG cultures produced significantly lower nitrite in response to LPS challenge than control MC/MG. IFN-γ-treated EAE mice had a significantly higher frequency of CX3CR1high MC/MG and expressed lower levels of program death ligand 1 (PD-L1) than PBS-treated mice. Most CX3CR1highPD-L1lowCD11b+Ly6G- cells expressed MG markers (Tmem119, Sall2, and P2ry12), indicating that they represented an enriched MG subset (CX3CR1highPD-L1low MG). Amelioration of clinical symptoms and induction of CX3CR1highPD-L1low MG by IFN-γ were dependent on STAT-1. RNA-seq analyses revealed that in vivo treatment with IFN-γ promoted the induction of homeostatic CX3CR1highPD-L1low MG, upregulating the expression of genes associated with tolerogenic and anti-inflammatory roles and down-regulating pro-inflammatory genes. These analyses highlight the master role that IFN-γ plays in regulating microglial activity and provide new insights into the cellular and molecular mechanisms involved in the therapeutic activity of IFN-γ in EAE.

Dataset Information

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

Publications

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

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