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.
Highlights
Mechanical cues are present in tissues throughout the body, and studies over the last several decades have shown that these signals play a major role in influencing cellular form and function [1, 2]
Given our own work identifying the importance of cell shape in regulating macrophage function [12], we first analyzed the role of cyclic forces in modulating macrophage cell morphology when compared to static controls (Figure 1A)
Macrophages stimulated with IFNg/LPS, adopted a flat and round cell shape, whereas macrophages stimulated with IL4/IL13, were elongated, as we have previously observed in macrophages cultured on other material surfaces [14]
Summary
Mechanical cues are present in tissues throughout the body, and studies over the last several decades have shown that these signals play a major role in influencing cellular form and function [1, 2]. Much less is known about how these forces influence immune cells, despite the fact that immune cells exist, function, and migrate throughout the body, including within mechanically active tissues [8]. Macrophages are innate immune cells that naturally reside within tissues, or are recruited from blood monocytes to tissues during injury or infection. These cells play a critical role in pathogen or damage surveillance and promoting inflammation and wound healing. This diversity in macrophage function stems from their ability to respond dynamically to cues in their microenvironment [9,10,11]. While the effects of soluble or biochemical stimuli, including pathogens- or damage-associated molecular patterns, cytokines, and chemokines on macrophage function are well- characterized, the role of physical stimuli in regulating macrophage function is not as well understood
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