2. Academic Validation
  3. TLR4 signalling via Piezo1 engages and enhances the macrophage mediated host response during bacterial infection

TLR4 signalling via Piezo1 engages and enhances the macrophage mediated host response during bacterial infection

  • Nat Commun. 2021 Jun 10;12(1):3519. doi: 10.1038/s41467-021-23683-y.
Jing Geng  # 1 2,  Yiran Shi  # 1,  Jinjia Zhang  # 1,  Bingying Yang 1,  Ping Wang 1,  Weihong Yuan 2,  Hao Zhao 1,  Junhong Li 1,  Funiu Qin 1,  Lixin Hong 1,  Changchuan Xie 1,  Xianming Deng 1,  Yujie Sun 3,  Congying Wu 4,  Lanfen Chen 5,  Dawang Zhou 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 2 National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 3 Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China.
  • 4 Institute of Systems Biomedicine, Peking University Health Science Center, Beijing, China.
  • 5 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. chenlanfen@xmu.edu.cn.
  • 6 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. dwzhou@xmu.edu.cn.
  • # Contributed equally.
PMID: 34112781 DOI: 10.1038/s41467-021-23683-y
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.

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