Signaling by the inhibitory receptor CD200R is rewired by type I interferon.

Autor:	van der Vlist M; Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., Ramos MIP; Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., van den Hoogen LL; Center for Translational Immunology, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Hiddingh S; Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands., Timmerman LM; Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., de Hond TAP; Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., Kaan ED; Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands., van der Kroef M; Center for Translational Immunology, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Lebbink RJ; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands., Peters FMA; Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands., Khoury-Hanold W; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA., Fritsch-Stork R; Center for Translational Immunology, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Radstake TRDJ; Center for Translational Immunology, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Meyaard L; Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.; Oncode Institute, Utrecht, Netherlands.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2021 Oct 12; Vol. 14 (704), pp. eabb4324. Date of Electronic Publication: 2021 Oct 12.
DOI:	10.1126/scisignal.abb4324
Abstrakt:	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:	MEDLINE
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