Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing

Hamza Atcha,Shivashankar Othy,Wendy F Liu,Medha M Pathak,Jesse R Holt,Raji R Nagalla,Vijaykumar S Meli,Kyle T Brumm,Amit Jairaman,Praveen Krishna Veerasubramanian,Huy E Lim,Michael D Cahalan

doi:10.1038/s41467-021-23482-5

Hamza Atcha, Shivashankar Othy + Show 10 more

Open Access

https://doi.org/10.1038/s41467-021-23482-5

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Abstract

Macrophages perform diverse functions within tissues during immune responses to pathogens and injury, but molecular mechanisms by which physical properties of the tissue regulate macrophage behavior are less well understood. Here, we examine the role of the mechanically activated cation channel Piezo1 in macrophage polarization and sensing of microenvironmental stiffness. We show that macrophages lacking Piezo1 exhibit reduced inflammation and enhanced wound healing responses. Additionally, macrophages expressing the transgenic Ca2+ reporter, Salsa6f, reveal that Ca2+ influx is dependent on Piezo1, modulated by soluble signals, and enhanced on stiff substrates. Furthermore, stiffness-dependent changes in macrophage function, both in vitro and in response to subcutaneous implantation of biomaterials in vivo, require Piezo1. Finally, we show that positive feedback between Piezo1 and actin drives macrophage activation. Together, our studies reveal that Piezo1 is a mechanosensor of stiffness in macrophages, and that its activity modulates polarization responses.

Highlights

Macrophages perform diverse functions within tissues during immune responses to pathogens and injury, but molecular mechanisms by which physical properties of the tissue regulate macrophage behavior are less well understood
We find that Piezo[1] activity promotes interferon-γ (IFNγ) and lipopolysaccharide (LPS)-induced inflammatory and suppresses interleukin-4 (IL4) and interleukin-13 (IL13)-induced healing responses
We found that bone marrow-derived macrophages (BMDMs) harvested from Piezo1ΔLysM mice have significantly reduced expression of the inflammatory marker inducible nitric oxide synthase in response to IFNγ/LPS stimulation when compared to BMDMs isolated from control Piezo1flox/+LysMCre/+ (Piezo1fl/+) mice (Fig. 1a)

Summary

Introduction

Macrophages perform diverse functions within tissues during immune responses to pathogens and injury, but molecular mechanisms by which physical properties of the tissue regulate macrophage behavior are less well understood. Pathogens and tissue damage polarize macrophages towards a “classically activated” state that promotes inflammation, whereas wound healing cytokines lead to an “alternatively activated”, anti-inflammatory state that aids in tissue repair[4]. In addition to such soluble stimuli, physical cues including tissue stiffness, matrix architecture, and mechanical stimulation are thought to contribute to macrophage function[5,6,7,8]. Piezo[1] regulates both stiffness-dependent changes in macrophage function in vitro and modulates the immune response to subcutaneous implantation of biomaterials in vivo. We show that positive feedback between Piezo[1] and actin drives macrophage activation

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