Abstract
TLR4 signaling plays key roles in the innate immune response to microbial infection. Innate immune cells encounter different mechanical cues in both health and disease to adapt their behaviors. However, the impact of mechanical sensing signals on TLR4 signal-mediated innate immune response remains unclear. Here we show that TLR4 signalling augments macrophage bactericidal activity through the mechanical sensor Piezo1. Bacterial infection or LPS stimulation triggers assembly of the complex of Piezo1 and TLR4 to remodel F-actin organization and augment phagocytosis, mitochondrion-phagosomal ROS production and bacterial clearance and genetic deficiency of Piezo1 results in abrogation of these responses. Mechanistically, LPS stimulates TLR4 to induce Piezo1-mediated calcium influx and consequently activates CaMKII-Mst1/2-Rac axis for pathogen ingestion and killing. Inhibition of CaMKII or knockout of either Mst1/2 or Rac1 results in reduced macrophage bactericidal activity, phenocopying the Piezo1 deficiency. Thus, we conclude that TLR4 drives the innate immune response via Piezo1 providing critical insight for understanding macrophage mechanophysiology and the host response.
Highlights
TLR4 signaling plays key roles in the innate immune response to microbial infection
We further revealed that LPS induces TLR4 to activate Piezo1-mediated calcium influx, which turns on the CaMKII-Mst1/2-Rac axis to enhance macrophage bactericidal activity
Higher amount of Piezo[1] was recruited and colocalized with TLR4 on the LPS-coated beads than that on the uncoated beads, whereas no obvious Piezo[1] or TLR4 could be detected on the beads engulfed in TLR4 deficient macrophages (Fig. 1c)
Summary
TLR4 signaling plays key roles in the innate immune response to microbial infection. Innate immune cells encounter different mechanical cues in both health and disease to adapt their behaviors. Bacterial infection or LPS stimulation triggers assembly of the complex of Piezo[1] and TLR4 to remodel F-actin organization and augment phagocytosis, mitochondrion-phagosomal ROS production and bacterial clearance and genetic deficiency of Piezo[1] results in abrogation of these responses. Inhibition of CaMKII or knockout of either Mst1/2 or Rac[1] results in reduced macrophage bactericidal activity, phenocopying the Piezo[1] deficiency. We report that the TLR4 coordinates the mechanical sensor Piezo[1] to activate CaMKII-Mst1/2 axis for coaxing macrophages into achieving the functions necessary for host defense. We further revealed that LPS induces TLR4 to activate Piezo1-mediated calcium influx, which turns on the CaMKII-Mst1/2-Rac axis to enhance macrophage bactericidal activity. We conclude that Piezo[1] governed mechanotransduction system is essential for TLR4-driven innate response against pathogen invasion
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