| Autor: |
van der Vlist, Michiel, Ramos, M. Inês Pascoal, van den Hoogen, Lucas L., Hiddingh, Sanne, Timmerman, Laura M., de Hond, Titus A. P., Kaan, Ellen D., van der Kroef, Maarten, Lebbink, Robert Jan, Peters, Florence M. A., Khoury-Hanold, William, Fritsch-Stork, Ruth, Radstake, Timothy R. D. J., Meyaard, Linde |
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| Zdroj: |
Science Signaling; 10/12/2021, Vol. 14 Issue 704, p1-11, 11p |
| Abstrakt: |
keyimage.jpg Interferon turns the tables: The inhibitory immunoreceptor CD200R dampens the TLR-dependent production of inflammatory cytokines by myeloid cells. Ligand-dependent CD200R signaling depends on the recruitment of an adaptor and the protein p120-RasGAP to its cytoplasmic tail. van der Vlist et al. found that treatment of human PBMCs with IFN-α resulted in the cleavage of p120-GAP, thus dysregulating CD200R signaling. Compared to PBMCs from healthy donors, those from patients with systemic lupus erythematosus, a disease characterized by high serum concentrations of IFN-α, had increased cleavage of p120-RasGAP. Furthermore, CD200R engagement enhanced, rather than reduced, the TLR-stimulated production of inflammatory cytokines. These data suggest that the type I IFN–dependent rewiring of CD200R signaling may underlie the inflammation seen in SLE patients. 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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