Substrate Viscoelasticity Amplifies Distinctions between Transient and Persistent LPS-Induced Signals

Macrophages settle in heterogeneous microenvironments comprising soluble or fixed biochemical components and biophysical clues rendered by other cells and extracellular matrices. It is well known that chemical stimuli direct macrophage behavior; however, the contributions of viscosity that are found to increase in inflammatory tissues but not in tumors are ignored in related immune responses including effective activation and timely attenuation. Herein, we show that transient lipopolysaccharide (LPS)-treated macrophages benefit from elastic substrates, while viscoelastic substrates with similar storage modulus support the inflammatory responses of macrophages under persistent stimulations and consequently amplify the distinctions between the transient and persistent LPS-induced transcriptional programs. Actin filaments (F-actin), direct responders to mechanical stimulations, fluctuate in line with transcriptional profiles and can be mathematically predicted by a clutch-like model. Moreover, F-actin levels dictate immune responses through transcription factors NF-κB and C/EBPδ, which act as switches discriminating between the transient and persistent infections. Interestingly, enhanced immune responses, as controlled as the lower activated macrophages, are attenuated timely by the actin nucleation-related translocation of ATF3 to nuclei. These findings suggest that substrate viscoelasticity induces more intense inflammation only in the case of persistent infection and serves as a key module for perceiving the duration of infection more sensitively through the F-actin correlated transcription factors. In addition, it may facilitate cognition to immune response in inflammatory and cancerous microenvironments and have a wide range of applications in inflammatory regulations.