Signaling by the inhibitory receptor CD200R is rewired by type I interferon
| Autor: | Sanne Hiddingh, Laura M. Timmerman, Timothy R D J Radstake, Robert Jan Lebbink, Ruth D E Fritsch-Stork, William Khoury-Hanold, Ellen D. Kaan, Michiel van der Vlist, F. Peters, Linde Meyaard, Lucas L van den Hoogen, M. Inês Pascoal Ramos, Maarten van der Kroef, Titus A. P. de Hond |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Chemistry
medicine.medical_treatment Interferon-alpha Inflammation Cell Biology mTORC1 TLR7 Acquired immune system Biochemistry Molecular biology Proinflammatory cytokine Cytokine Interferon Interferon Type I Leukocytes Mononuclear medicine Humans medicine.symptom Receptor Molecular Biology Adaptor Proteins Signal Transducing Signal Transduction medicine.drug |
| Zdroj: | Science Signaling. 14 |
| ISSN: | 1937-9145 1945-0877 |
| Popis: | CD200 receptor 1 (CD200R) is an inhibitory immunoreceptor that suppresses Toll-like receptor (TLR)–induced cytokine production through the adaptor protein Dok2 and the GTPase activating protein (GAP) p120-RasGAP, which can be cleaved during mild cellular stress. We found that in the presence of cleaved p120-RasGAP, CD200R lost its capacity to inhibit phosphorylation of ribosomal S6 protein (rpS6), suggesting the reduced activity of mammalian target of rapamycin complex 1 (mTORC1). Furthermore, treatment of human peripheral blood mononuclear cells (PBMC) with interferon-α (IFN-α) resulted in increased amounts of cleaved p120-RasGAP. Upon pretreatment of cells with increasing concentrations of IFN-α, CD200R switched from inhibiting to potentiating the TLR7- and TLR8-induced expression of the gene encoding IFN-γ, a cytokine that is important for innate and adaptive immunity and is implicated in systemic lupus erythematosus (SLE) pathogenesis. PBMC from patients with SLE, a prototypic type I IFN disease, had an increased abundance of cleaved p120-RasGAP compared to that in cells from healthy controls. In a subset of SLE patients, CD200R stopped functioning as an inhibitory receptor or potentiated TLR-induced IFNG mRNA expression. Thus, our data suggest that type I IFN rewires CD200R signaling to be proinflammatory, which could contribute to the perpetuation of inflammation in patients with SLE. |
| Databáze: | OpenAIRE |
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