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.

Keywords: MRTF; macrophage; mechanobiology; microgravity; multiscale; radiation.

FIGURE 1

Some Mϕ spaceflight effects require more time or space. An overview of the altered spaceflight exposome (gravity, cytoskeleton, intracellular transport, hypoxia, radiation, intercellular signaling) and hypothetically relevant sensors and effector proteins: (LPS—lipopolysaccharide, TLR-4—t oll-like receptor 4, G-actin—globular actin, F-actin—filamentous actin, microtubules, dynein, p53—tumor protein P53, p38—mitogen-activated protein kinase p38, MRTF—myocardin-related transcription factor-A or megakaryoblastic leukemia 1 (MKL1), SRF—serum response factor, NF-κB/p65—nuclear factor kappa-light-chain-enhancer of activated B cells (p65 or RelA), IL-6—interleukin 6, IL-12, TNF-α—tumor necrosis factor-alpha, osteopontin, ICAM-1—intercellular adhesion molecule-1, miRNA—(microRNA such as miR-21—microRNA-21-5p). Spatial variation occurs across molecular, cellular, and physiological scales (increasing space). Time variation occurs from seconds in microgravity to months from long-term radiation (increasing time). Effects are not mutually exclusive and may interact at multiple scales, i.e., microgravity first acts alone and later acts in conjunction with radiation. Created with BioRender.com. *Parabolic Flight, †Simulated microgravity culture vessel (not flight), ‡Long-term orbital spaceflight.

FIGURE 2

Mechanotransduction is inherently involved in Mϕ activation in a time-dependent manner. Under controlled conditions, LPS induces TLR4 “outside-in” signaling in the first few hours of activation. Sustained LPS induces “inside-out” signaling, resulting in activation of ion-channels and actin reorganization. This causes a second mechanotransductive phase via the accumulation of MRTF-A. The present figure depicts the current knowledge about MRTF in Mϕ activation, but many pathways are simplified for clarity. The complicated involvement of cellular mechanical mechanisms (LINC—linker of nucleoskeleton and cytoskeleton, emerin, ERK—extracellular signal-regulated kinase, YAP/TAZ—yes-associated protein/transcriptional coactivator with PDZ domain), or physical environments (substrate stiffness, spatial confinement, microgravity) alters the extent of Mϕ activation. The bidirectional interaction of p65 and MRTF does not fully inhibit them as some late-transcriptional genes are promoted by the p65 & MRTF complex e.g., iNOS (Miranda et al., 2021). Created with BioRender.com. *(Bian et al., 2017; Mu, 2018; Ronzier et al., 2022). ‡(Wang C. et al., 2015). §MRTF-A epigenetic regulation of ICAM-1 is likely dependent on cell type (Sullivan et al., 2011; Yu et al., 2014; Miranda et al., 2021) and is not known in Mϕ. ‖(Hoffman et al., 2020).