MRTF May Be the Missing Link in a Multiscale Mechanobiology Approach toward Macrophage Dysfunction in Space

Macrophages exhibit impaired phagocytosis, adhesion, migration, and cytokine production in space, hindering their ability to elicit immune responses. The combined effect of spaceflight microgravity and radiation on macrophage dysfunction is multiscale and multifactorial in nature. However, spaceflight and simulated microgravity experiments often take single-scale approaches. This hypothesis and theory paper reanalyzes research in the macrophage spaceflight response across multiple scales, from the molecular, intracellular, extracellular, to the physiological. Here, we introduce the time-dependent, mechanotransducive MRTF-A/SRF pathway, which depends on intracellular localization, to elucidate seemingly contradictory macrophage responses across time scales. We discuss the MRTF-A/SRF pathway dependence on the actin cytoskeleton/nucleoskeleton, microtubules, mechanosensitive membrane proteins, hypoxia, oxidative stress, and crosstalk with other pathways and cells. By adopting a multiscale perspective, this paper identifies potential mechanisms for adverse macrophage responses and strengthens the connection between microgravity, mechanobiology, and the spaceflight immune response. Finally, we hypothesize MRTF involvement and complications in treating spaceflight-induced cardiovascular, skeletal, and immune disease.