TY - JOUR
T1 - Signaling cascade through DC-AsGPR induces transcriptionally active CREB for IL-10 induction and immune regulation
AU - Gu, Chao
AU - Wang, Lei
AU - Zurawski, Sandra
AU - Oh, Sang Kon
N1 - Publisher Copyright:
Copyright Ó 2019 by The American Association of Immunologists, Inc.
PY - 2019
Y1 - 2019
N2 - The types and magnitude of Ag-specific immune responses can be determined by the functional plasticity of dendritic cells (DCs). However, how DCs display functional plasticity and control host immune responses have not been fully understood. In this study, we report that ligation of DC–asialoglycoprotein receptor (DC-ASGPR), a C-type lectin receptor (CLR) expressed on human DCs, resulted in rapid activation of Syk, followed by PLCg2 and PKCd engagements. However, different from other Syk-coupled CLRs, including Dectin-1, signaling cascade through DC-ASGPR did not trigger NF-kB activation. Instead, it selectively activated MAPK ERK1/2 and JNK. Rapid and prolonged phosphorylation of ERK1/2 led to sequential activation of p90RSK and CREB, which consequently bound to IL10 promoter and initiated cytokine expression. In addition, DC-ASGPR ligation activated Akt, which differentially regulated the activities of GSK-3a/b and b-catenin and further contributed to IL-10 expression. Our observations demonstrate that DC-ASGPR induces IL-10 expression via an intrinsic signaling pathway, which provides a molecular explanation for DC-ASGPR–mediated programing of DCs to control host immune responses.
AB - The types and magnitude of Ag-specific immune responses can be determined by the functional plasticity of dendritic cells (DCs). However, how DCs display functional plasticity and control host immune responses have not been fully understood. In this study, we report that ligation of DC–asialoglycoprotein receptor (DC-ASGPR), a C-type lectin receptor (CLR) expressed on human DCs, resulted in rapid activation of Syk, followed by PLCg2 and PKCd engagements. However, different from other Syk-coupled CLRs, including Dectin-1, signaling cascade through DC-ASGPR did not trigger NF-kB activation. Instead, it selectively activated MAPK ERK1/2 and JNK. Rapid and prolonged phosphorylation of ERK1/2 led to sequential activation of p90RSK and CREB, which consequently bound to IL10 promoter and initiated cytokine expression. In addition, DC-ASGPR ligation activated Akt, which differentially regulated the activities of GSK-3a/b and b-catenin and further contributed to IL-10 expression. Our observations demonstrate that DC-ASGPR induces IL-10 expression via an intrinsic signaling pathway, which provides a molecular explanation for DC-ASGPR–mediated programing of DCs to control host immune responses.
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U2 - 10.4049/jimmunol.1900289
DO - 10.4049/jimmunol.1900289
M3 - Article
C2 - 31175164
AN - SCOPUS:85068897284
SN - 0022-1767
VL - 203
SP - 389
EP - 399
JO - Journal of Immunology
JF - Journal of Immunology
IS - 2
ER -