Phosphoinositide 3-Kinase δ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity

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.

Section: Dc-asgpr Activates Akt That Differentially Regulates the Actmentioning

confidence: 99%

Signaling Cascade through DC-ASGPR Induces Transcriptionally Active CREB for IL-10 Induction and Immune Regulation

Wang

Zurawski

et al. 2019

“…Several studies have addressed the structural requirements for interaction of Mincle with the mycobacterial cord factor trehalose dimycolate (TDM) or synthetic trehalose esters (70)(71)(72)(73)(74), which have recently been summarized in excellent reviews (75)(76)(77). Mincle binds the trehalose part of the cord factor with its Ca 2+dependent sugar-binding pocket, and its structure revealed a (50,106). Both Dectin-2 and Mincle ligation can lead to production of ROS and inflammasome activation (107)(108)(109)(110)(111)(112).…”

Section: Clrs and Tlrs Activate Distinct Inflammatory Pathways And Gementioning

confidence: 99%

Contact, Collaboration, and Conflict: Signal Integration of Syk-Coupled C-Type Lectin Receptors

Ostrop

Lang

2017

conducted on CLR assigned to the so-called Dectin-1 or Dectin-2 clusters, localized within 51 the NK cell gene cluster on human chromosome 12 or mouse chromosome 6 (1-3). Several 52 excellent reviews on the function of these CLR in anti-microbial defense and homeostasis are 53 available (4, 5). In this review we summarize the current knowledge about signaling 54 downstream of the activating CLR Dectin-1 (Clec7a), Dectin-2 (human Clec6a, mouse 55 Clec4n), Mincle (Clec4e) and Mcl (Clec4d) that is largely dependent on the kinase spleen 56 tyrosine kinase (Syk). Table I provides an overview of defined ligands and microorganisms 57 bound by this group of PRR. In addition to microbial carbohydrate and glycolipid structures 58 acting as PAMP, several CLR bind endogenous ligands such as SAP130 released by dying 59 cells or cholesterol crystals. Thus, these CLR are involved in homeostatic responses and 60 inflammatory conditions (6-9), in addition to host response to pathogens and commensals (10-61 (Fig. 1). 103 Syk-Card9 coupled CLR is observed across cell-types and species, promoting the 111 differentiation of IL-17-producing CD4+ T cells (23, 24, 26, 27). Remarkably, to date there is 112 only very limited information about the effects of combined stimulation of CLR and TLR 113 pathways on global gene expression. 114

“…7A). Another cellular pathway, the PI3K/PKC signaling axis, was known to play key roles in fungal modulation of host responses; however, its networking with other signaling pathways in these scenarios was poorly explored (54). Using their inhibitors LY294002 and rottlerin, we found C. albicans-elicited BMP signaling was abrogated when PI3K or PKCd axis were intercepted ( Fig.…”

Section: Albicans-dependent Activation Of Pi3k Signaling Drives Bmmentioning

confidence: 99%

Deregulated AUF1 Assists BMP-EZH2–Mediated Delayed Wound Healing during Candida albicans Infection

Mahadik

Yadav

Bhatt

et al. 2018

Tissue repair is a complex process that necessitates an interplay of cellular processes, now known to be dictated by epigenetics. Intriguingly, macrophages are testimony to a large repertoire of evolving functions in this process. We identified a role for BMP signaling in regulating macrophage responses to Candida albicans infection during wound repair in a murine model. In this study, the RNA binding protein, AU-rich element–binding factor 1, was posttranslationally destabilized to bring about ubiquitin ligase, NEDD4-directed activation of BMP signaling. Concomitantly, PI3K/PKCδ mobilized the rapid phosphorylation of BMP-responsive Smad1/5/8. Activated BMP pathway orchestrated the elevated recruitment of EZH2 at promoters of genes assisting timely wound closure. In vivo, the repressive H3K27 trimethylation was observed to persist, accompanied by a robust upregulation of BMP pathway upon infection with C. albicans, culminating in delayed wound healing. Altogether, we uncovered the signaling networks coordinated by fungal colonies that are now increasingly associated with the infected wound microbiome, resulting in altered wound fate.