MRTF may be the missing link in a multiscale mechanobiology approach toward macrophage dysfunction in space

Abstract

Macrophages exhibit impaired phagocytosis, adhesion, migration, and cytokine production in space, hindering their ability to elicit immune responses. Considering that the combined effect of spaceflight microgravity and radiation is multiscale and multifactorial in nature, it is expected that contradictory findings are common in the field. This theory paper reanalyzes research on the macrophage spaceflight response across multiple timescales from seconds to weeks, and spatial scales from the molecular, intracellular, extracellular, to the physiological. Key findings include time-dependence of both pro-inflammatory activation and integrin expression. Here, we introduce the time-dependent, intracellular localization of MRTF-A as a hypothetical confounder of macrophage activation. We discuss the mechanosensitive MRTF-A/SRF pathway dependence on the actin cytoskeleton/nucleoskeleton, microtubules, membrane mechanoreceptors, hypoxia, oxidative stress, and intracellular/extracellular crosstalk. By adopting a multiscale perspective, this paper provides the first mechanistic answer for a three-decade-old question regarding impaired cytokine secretion in microgravity—and strengthens the connection between the recent advances in mechanobiology, microgravity, and the spaceflight immune response. Finally, we hypothesize MRTF involvement and complications in treating spaceflight-induced cardiovascular, skeletal, and immune disease.

Influence of the spaceflight environment on macrophage lineages

“…In line with this, the FAK-ERK1/2 signaling pathway involved in actin polymerization and multiple other signal transduction cascades, is downregulated in HPC concomitantly differentiating into macrophages (12-day differentiation process) both in simulated microgravity conditions (12-days) and spaceflight (12-day mission) 24 , indicating aberrant cell signaling, impaired macrophage maturation, and cytoskeletal disturbances are influenced by the microgravity environment. In line with this, signaling pathways such as STAT3, P38, JNK, FAK-ERK, Rho/ROCK, AKT, CREB, NF-κB, RAC-WAVE-Arp2/3 (reviewed in 63 , 64 ) and MRTF-A/SRF (reviewed in 64 , 65 ), may all be engaged in microgravity, which also requires further studies.…”