The kinetics of signaling through the common FcRγ chain determine cytokine profiles in dendritic cells

Abstract

The common Fc receptor γ (FcRγ) chain is a signaling subunit common to several immune receptors, but cellular responses induced by FcRγ-coupled receptors are diverse. We investigated the mechanisms by which FcRγ generates divergent signals when coupled to Dectin-2 and Mincle, structurally similar C-type lectin receptors that induce the release of different cytokines from dendritic cells. Chronological tracing of transcriptomic and epigenetic changes upon stimulation revealed that Dectin-2 induced early and strong signaling, whereas Mincle-mediated signaling was delayed, which reflects their expression patterns. Generation of early and strong FcRγ-Syk signaling by engineered chimeric receptors was sufficient to recapitulate a Dectin-2–like gene expression profile. Early Syk signaling selectively stimulated the activity of the calcium ion–activated transcription factor NFAT, which rapidly altered the chromatin status and transcription of the Il2 gene. In contrast, proinflammatory cytokines, such as TNF, were induced regardless of FcRγ signaling kinetics. These results suggest that the strength and timing of FcRγ-Syk signaling can alter the quality of cellular responses through kinetics-sensing signaling machineries.

Straight to the point: targeted mRNA-delivery to immune cells for improved vaccine design

“…These receptors include pathogen recognition receptors (PRR) like C-type lectin receptors (CLRs), a superfamily of proteins that interact with several types of sugars on the surface of pathogens and have a crucial role in the capture and presentation of the antigen, and Toll-like receptors (from TLR1 to TLR10), both primarily involved in the recognition of pathogen-associated molecular patterns (PAMPs) ( 28 ). DCs also express Scavenger receptors like CD36 ( 29 , 30 ) involved in the uptake of a variety of ligands, including lipids, apoptotic cells, and microbial components as well as several other receptors such as chemokines receptors, complement receptors and Fc receptors, all regulating antigen presentation functions ( 31 ). In the sections that follow, we provide a more detailed description of such receptors and their respective ligands.…”

“…Macrophages express several receptors that that could be targeted for vaccine delivery such as TLRs ( 28 ), mannose receptors ( 86 ), scavenger receptors ( 29 ) and Fc receptors ( 31 ). Targeting this cell population is particularly interesting for respiratory infections, since alveolar macrophages are the first cells to present pathogens to pulmonary draining lymph nodes ( 87 ).…”

“…Details of CLR signaling and their immunological outcomes have been brilliantly reviewed elsewhere ( 100 , 105 ). Interestingly, although many CLRs share this signaling pathway, they all lead to specific responses; recently, fascinating reports were published revealing how kinetics and information transfer of similar lectins allow for their different biochemical outcomes ( 31 , 106 ). The second group of CLRs, on the other hand, bear on their cytoplasmic end an Immunoreceptor Tyrosine-based inhibition (ITIM) motif (e.g.…”

Archaeal Glycerolipids Are Recognized by C-Type Lectin Receptor Mincle

“…We reported previously that the quantity and duration of FcRγ signaling may induce distinct signaling through the common FcRγ subunit. 42,48,49 Considering these findings, the differences in ligand structures may affect the kinetics and strength of Mincle-FcRγ signaling, potentially generating different gene expression profiles. Further research is necessary to understand their effects on host biological processes, including the immune system.…”

SIRPB1 regulates inflammatory factor expression in the glioma microenvironment via SYK: functional and bioinformatics insights

“…Our study of a single-cell dataset using the signaling pathway of the IL1RN gene showed that IL1RN expression in glioma-associated macrophages changes from low to high. TNF, NF-κB, osteoclast differentiation, and SYK pathways may explain these findings [ 69 ]. We speculate that after SIRPB1 deletion, inadequate early SYK phosphorylation could impact downstream pathways.…”