Crosstalk Between CD11b and Piezo1 Mediates Macrophage Responses to Mechanical Cues

Abstract

Macrophages are versatile cells of the innate immune system that perform diverse functions by responding to dynamic changes in their microenvironment. While the effects of soluble cues, including cytokines and chemokines, have been widely studied, the effects of physical cues, including mechanical stimuli, in regulating macrophage form and function are less well understood. In this study, we examined the effects of static and cyclic uniaxial stretch on macrophage inflammatory and healing activation. We found that cyclic stretch altered macrophage morphology and responses to IFNγ/LPS and IL4/IL13. Interestingly, we found that both static and cyclic stretch suppressed IFNγ/LPS induced inflammation. In contrast, IL4/IL13 mediated healing responses were suppressed with cyclic but enhanced with static stretch conditions. Mechanistically, both static and cyclic stretch increased expression of the integrin CD11b (αM integrin), decreased expression of the mechanosensitive ion channel Piezo1, and knock down of either CD11b or Piezo1 through siRNA abrogated stretch-mediated changes in inflammatory responses. Moreover, we found that knock down of CD11b enhanced the expression of Piezo1, and conversely knock down of Piezo1 enhanced CD11b expression, suggesting the potential for crosstalk between integrins and ion channels. Finally, stretch-mediated differences in macrophage activation were also dependent on actin, since pharmacological inhibition of actin polymerization abrogated the changes in activation with stretch. Together, this study demonstrates that the physical environment synergizes with biochemical cues to regulate macrophage morphology and function, and suggests a role for CD11b and Piezo1 crosstalk in mechanotransduction in macrophages.

Mechanical force modulates macrophage proliferation via Piezo1‐AKT‐Cyclin D1 axis

“…Macrophages are sensitive to mechanical stimuli, and affect their biological behavior by converting mechanical signals into cellular messages depending on various mechanosensors 30 . Mechanosensitive ion channels mediated Ca 2+ influx has been identified as a key second messenger in macrophage polarization 14,31 . The reduction of alveolar surface tension in vivo could regulate the shape of cells and increase the phagocytic activity of alveolar macrophages 32 .…”

Implications of considering peri‐implant bone loss a disease, a narrative review

“…84 In addition, a recent study demonstrated that there is a synergy between cellular mechanotransduction and biochemical signals in the regulation of macrophages which would be related to CD11b and Piezo1 crosstalk. 85 In this context it has been proposed that shockwave-induced immunomodulation has potential as a non-invasive physical therapy to regulate macrophage functions linked with wound healing 86 and osseointegration. 78,79,87 This could be a biological mechanism behind the re-fixation of orthopedic implants.…”

“…It has recently been proposed that mechanical stimulation could promote the conversion of myeloid‐derived monocytes into an activated status, suggesting that occlusal force might determine the immune microenvironment of the alveolar bone 84 . In addition, a recent study demonstrated that there is a synergy between cellular mechano‐transduction and biochemical signals in the regulation of macrophages which would be related to CD11b and Piezo1 crosstalk 85 . In this context it has been proposed that shockwave‐induced immunomodulation has potential as a non‐invasive physical therapy to regulate macrophage functions linked with wound healing 86 and osseointegration 78,79,87 .…”

The contribution of ion channels to shaping macrophage behaviour

“…Finally, a novel mechanically-activated cation channel Piezo1 has been reported in macrophages. Piezo1 roles are proposed to include mechanical stimuli sensing, potentially via Piezo1 and integrins crosstalk and modulation of macrophage polarization ( Atcha et al, 2021a ; Atcha et al, 2021b ), toll-like receptor 4-mediated enhancement of macrophage bactericidal activity ( Geng et al, 2021 ) and macrophage migration (unpublished data). Recently, this channel has also been demonstrated to be a key regulator of erythrocyte phagocytosis by macrophages and iron metabolism ( Ma et al, 2021 ).…”