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- Title
Signaling by the inhibitory receptor CD200R is rewired by type I interferon.
- Authors
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
- Abstract
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.
- Subjects
TYPE I interferons; INTERFERON receptors; MONONUCLEAR leukocytes; GENE expression; RIBOSOMAL proteins; MYELOID cells; ADAPTOR proteins; MTOR protein
- Publication
Science Signaling, 2021, Vol 14, Issue 704, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abb4324