Amplification of IFN-α-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors

Tassiulas, Ioannis; Hu, Xiaoyu; Ho, Hao; Kashyap, Yogita; Paik, Paul K.; Hu, Yongmei; Lowell, Clifford A.; Ivashkiv, Lionel B.

doi:10.1038/ni1126

Cited by 91 publications

(85 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, entry through the activating FcγR pathway would pose no replicative benefit to DENV unless it is able to overcome the ITAM-Syk-STAT-1 signaling axis that leads to ISG induction (7,13). The findings here thus indicate that coligation of LILRB1 is a critical first step for successful antibody-dependent DENV infection (SI Appendix, Fig.…”

Section: Discussionmentioning

confidence: 83%

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

Chan

Ong

Tan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

104

View full text Add to dashboard Cite

Viruses must evade the host innate defenses for replication and dengue is no exception. During secondary infection with a heterologous dengue virus (DENV) serotype, DENV is opsonized with sub-or nonneutralizing antibodies that enhance infection of monocytes, macrophages, and dendritic cells via the Fc-gamma receptor (FcγR), a process termed antibody-dependent enhancement of DENV infection. However, this enhancement of DENV infection is curious as cross-linking of activating FcγRs signals an early antiviral response by inducing the type-I IFN-stimulated genes (ISGs). Entry through activating FcγR would thus place DENV in an intracellular environment unfavorable for enhanced replication. Here we demonstrate that, to escape this antiviral response, antibody-opsonized DENV coligates leukocyte Ig-like receptor-B1 (LILRB1) to inhibit FcγR signaling for ISG expression. This immunoreceptor tyrosine-based inhibition motif-bearing receptor recruits Src homology phosphatase-1 to dephosphorylate spleen tyrosine kinase (Syk). As Syk is a key intermediate of FcγR signaling, LILRB1 coligation resulted in reduced ISG expression for enhanced DENV replication. Our findings suggest a unique mechanism for DENV to evade an early antiviral response for enhanced infection.early innate immune response | innate immune signaling | immune evasion D espite long-lived serotype-specific immunity upon initial infection, predicted global prevalence of dengue now surpasses World Health Organization estimates by more than threefold with 390 million cases annually (1). Furthermore, the risk of severe disease is augmented by cross-reactive or subneutralizing levels of antibody (2, 3), which opsonize dengue virus (DENV) to ligate Fc-gamma receptor (FcγR) for entry into monocytes, macrophages, and dendritic cells, a phenomenon known as antibody-dependent enhancement (ADE) of DENV infection (4, 5). The resultant greater viral burden leads to increased systemic inflammation that precipitates plasma leakage, a hallmark of dengue hemorrhagic fever (6). However, ligation of the activating FcγRs by immune complexes has been shown to induce type-I IFN stimulated genes (ISGs), independent of autocrine or paracrine IFN activity, unless the inhibitory FcγRIIB is coligated (7). We and others reported recently that coligation of FcγRIIB by DENV immune complexes requires high antibody concentration, and such coligation inhibited the entry of DENV immune complexes into monocytes (8, 9). At low antibody concentrations where ADE occurs, the inhibitory FcγRIIB is not coligated (9). Ligation of the activating FcγRs by DENV opsonized with subneutralizing levels of antibody would thus induce the expression of ISGs and hinder DENV replication (10). Here, we demonstrate that DENV employs a unique evasive mechanism by coligating LILRB1 to down-regulate the early antiviral responses triggered by activating FcγRs for ADE.Results ADE Differs in THP-1 Subclones. Our work was enabled by the isolation of subclones of THP-1 cells with different phenotypes to ADE. The low rate of...

show abstract

Section: Discussionmentioning

confidence: 83%

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

Chan

Ong

Tan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

104

View full text Add to dashboard Cite

show abstract

“…Priming with IFN-␥ increased the levels of IFN-␣-induced STAT1 homodimers or ISGF3 but decreased IFN-␥-induced STAT1 ho- modimers (16). Tassiulas et al (25) showed that a high level of STAT1 was not sufficient to enhance IFN-␣-induced STAT1 activation and gene expression after IFN-␥-priming, but the tyrosine kinase Syk and immunoreceptor tyrosine activation motifs were required. In clinical data, the expression level of STAT1 does not influence the response to IFN-␣ adjuvant therapy for cancer patients, and STAT1 levels were even greater in recurrent tumors compared with original tumors (26).…”

Section: Discussionmentioning

confidence: 99%

Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes

Cheon

Stark

2009

Proc. Natl. Acad. Sci. U.S.A.

271

259

View full text Add to dashboard Cite

In normal human cells treated with interferons (IFNs), the concentration of tyrosine-phosphorylated STAT1 (YP-STAT1), which drives the expression of a large number of genes, increases quickly but then decreases over a period of several hours. Because the STAT1 gene is activated by YP-STAT1, IFNs stimulate a large increase in the concentration of unphosphorylated STAT1 (U-STAT1) that persists for several days. To test the significance of high U-STAT1 expression, we increased its concentration exogenously in the absence of IFN treatment. In response, the expression of many immune regulatory genes (e.g., IFI27, IFI44, OAS, and BST2) was increased. In human fibroblasts or mammary epithelial cells treated with low concentrations of IFN-␤ or IFN-␥, the expression of the same genes increased after 6 h and continued to increase after 48 or 72 h, long after the concentration of YP-STAT1 had returned to basal levels. Consistent with its activity as a transcription factor, most U-STAT1 was present in the nuclei of these cells before IFN treatment, and the fraction in nuclei increased 48 h after treatment with IFN. We conclude that the nuclear U-STAT1 that accumulates in response to IFNs maintains or increases the expression of a subset of IFN-induced genes independently of YP-STAT1, and that many of the induced proteins are involved in immune regulation. Their signaling pathways are mediated by the sequential phosphorylation of Janus family kinases (JAKs) and STATs. Type I IFNs phosphorylate STATs 1 and 2, which form IFN-stimulated gene factor-3 (ISGF-3), a ternary complex that also includes IFN response factor-9 (IRF9). IFN-␥ induces the phosphorylation of STAT1, which forms STAT1 homodimers. These activated transcription factors translocate into the nucleus, where they bind to distinct conserved sequences in the promoters of target genes. However, recent studies have shown that IFN signaling is much more complex (2). IFNs activate several different kinases in addition to the JAKs, other STATs in addition to STAT1 and STAT2, and even other transcription factors (3-9).Our previous work has shown that STAT1 drives the constitutive expression of some genes without phosphorylation (10, 11). For example, the complex of unphosphorylated STAT1 (U-STAT1) and IRF1 mediates the constitutive expression of the low-molecular mass polypeptide 2 (LMP2) gene (11). Similarly, Cui et al. (12) have shown that unphosphorylated STAT6 cooperates with p300 to increase transcription of the cyclooxygenase-2 gene. Initially, unphosphorylated STATs were considered to be latent transcription factors in the cytoplasm, entering the nucleus to induce gene expression only in response to cytokine stimulation. However, consistent with our previous results, STAT1 and STAT3 have been found to be present in nuclei independently of tyrosine phosphorylation, in a cell type-specific manner, and the nuclear import mechanism of U-STAT1 is completely distinct from that of phosphorylated STAT1 (13, 14). The nuclear import of tyrosinephosphorylated STAT1 dimers dep...

show abstract

“…First, because ISGs are genes that should be inducible by IFN-I, such as IFN-a treatment, we filtered the ISGs, which exhibited .4-fold increase in expression in response to IFN-a treatment, based on publically deposited microarray data (Gene Expression Omnibus ID E-GEOD-1740, Fig. 1A, x-axis) (25). Second, the disease-related regulatory ISGs should be more significantly upregulated in progressors than in nonprogressors.…”

Section: Identification Of Hiv-1 Disease-associated Regulatory Isgsmentioning

confidence: 99%

IFN-Stimulated Gene LY6E in Monocytes Regulates the CD14/TLR4 Pathway but Inadequately Restrains the Hyperactivation of Monocytes during Chronic HIV-1 Infection

Qiu

Zhu

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Owing to ongoing recognition of pathogen-associated molecular patterns, immune activation and upregulation of IFN-stimulated genes (ISGs) are sustained in the chronically infected host. Albeit most ISGs are important effectors for containing viral replication, some might exert compensatory immune suppression to limit pathological dysfunctions, although the mechanisms are not fully understood. In this study, we report that the ISG lymphocyte Ag 6 complex, locus E (LY6E) is a negative immune regulator of monocytes. LY6E in monocytes negatively modulated CD14 expression and subsequently dampened the responsiveness to LPS stimulation in vitro. In the setting of chronic HIV infection, the upregulation of LY6E was correlated with reduced CD14 level on monocytes; however, the immunosuppressive effect of LY6E was not adequate to remedy the hyperresponsiveness of activated monocytes. Taken together, the regulatory LY6E pathway in monocytes represents one of negative feedback mechanisms that counterbalance monocyte activation, which might be caused by LPS translocation through the compromised gastrointestinal tract during persistent HIV-1 infection and may serve as a potential target for immune intervention.

show abstract

Amplification of IFN-α-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors

Cited by 91 publications

References 58 publications

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes

IFN-Stimulated Gene LY6E in Monocytes Regulates the CD14/TLR4 Pathway but Inadequately Restrains the Hyperactivation of Monocytes during Chronic HIV-1 Infection

Contact Info

Product

Resources

About