YAP-mediated mechanotransduction tunes the macrophage inflammatory response

Abstract

Macrophages are innate immune cells that adhere to the extracellular matrix within tissues. However, how matrix properties regulate their function remains poorly understood. Here, we report that the adhesive microenvironment tunes the macrophage inflammatory response through the transcriptional coactivator YAP. We find that adhesion to soft hydrogels reduces inflammation when compared to adhesion on stiff materials and is associated with reduced YAP expression and nuclear localization. Substrate stiffness and cytoskeletal polymerization, but not adhesive confinement nor contractility, regulate YAP localization. Furthermore, depletion of YAP inhibits macrophage inflammation, whereas overexpression of active YAP increases inflammation. Last, we show in vivo that soft materials reduce expression of inflammatory markers and YAP in surrounding macrophages when compared to stiff materials. Together, our studies identify YAP as a key molecule for controlling inflammation and sensing stiffness in macrophages and may have broad implications in the regulation of macrophages in health and disease.

Cell-adaptable dynamic hydrogel reinforced with stem cells improves the functional repair of spinal cord injury by alleviating neuroinflammation

“…It has been reported that soft implant materials reduce expression of inflammatory markers in surrounding macrophages when compared to stiff materials [44] and ADSCs may play an important role in immunomodulation by secreting paracrine signals [45].…”

“…Meli et al [44] reported that a soft hydrogel matrix enhanced adhesion and suppressed the M1 polarization of macrophages. Previous studies have also demonstrated the immunomodulatory potential of ADSCs via paracrine signals, including growth factors, cytokines, and exosomes [45].…”

An Updated Understanding of the Role of YAP in Driving Oncogenic Responses

“…Almost all cellular signals that have YAP as a main downstream target effector (i.e., mechanotransduction, Rho GTPase, Wnt signaling, inflammation and metabolic variation [ 77 , 81 , 85 , 86 , 87 , 88 , 89 , 90 ]) ( Figure 3 ) are highly involved in the regulation of tissue repair, and by referring to cancers as “wounds that do not heal”, the prominent involvement of YAP in the regulation of tumor growth appears logical [ 91 ]. Accordingly, sustained cell proliferation is among the best characterized YAP-driven biological responses, emphasizing its remarkable involvement in tissue development by directly acting on the amplification of progenitor cells.…”

Biomaterials-assisted spheroid engineering for regenerative therapy

“…Future studies should consider tailoring physical features of scaffolds (e.g., stiffness, topography, mechanical stability, and degradation profiles) that compensate dynamic mechanical alterations of injured tissues. There is emerging evidence that physical cues applied to injured tissues are critical to regulate tissue repair and even immune responses via mechanotransduction ( 94 - 97 ). However, their roles in 3D spheroids have not been fully investigated yet.…”