Spatiotemporal Regulation of Ligand Trafficking and TLR9 Activation by PIEZO1 in Human Plasmacytoid Dendritic Cells

TL;DR

This study shows how a mechanosensory ion channel, PIEZO1, regulates immune responses in dendritic cells by controlling how different DNA-like molecules activate immune signals.

Contribution

PIEZO1 is identified as a novel mechanosensor that controls TLR9 signaling through membrane tension and spatial regulation in pDCs.

Findings

CpGA forms aggregates that activate PIEZO1, leading to sustained IFN production in pDCs.

PIEZO1 deficiency or inhibition reduces CpGA-induced IFN responses.

PIEZO1 activation can enhance IFN production from CpGB, which normally induces weaker responses.

Abstract

Plasmacytoid dendritic cells (pDCs) are innate immune cells that produce type I interferons (IFNs) upon sensing nucleic acids via Toll-like receptor 9 (TLR9). Synthetic oligodeoxynucleotides CpGA and CpGB are widely used TLR9 agonists, yet only CpGA robustly induces IFN-α in pDCs. In contrast, CpGB drives much less IFN production. The mechanism underlying this ligand-specific response is not known. Here, we identify PIEZO1, a mechanosensory ion channel, as a regulator for this ligand-specific response. We show that CpGA, unlike CpGB, self-associates into large aggregates that generate membrane tension during cellular uptake, activating PIEZO1. This triggers calcium influx and localized F-actin assembly, retaining CpGA in early endosomes to sustain IRF7 activation and IFN production. PIEZO1 deficiency or inhibition abolishes CpGA-induced IFN responses, while PIEZO1 activation enhances IFN production by CpGB. Our findings reveal a hitherto unknown biophysical checkpoint in TLR9 signaling, where PIEZO1 translates membrane tension into spatially controlled TLR9 signaling. This study uncovers a novel role for mechanosensing in nucleic acid immunity, with implications for modulating IFN responses in infections and autoimmunity.

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