Manipulating immune activity of macrophages: a materials and mechanics perspective

Abstract

Macrophage immune cells exist on a plastic spectrum of phenotypes governed by their physical and biochemical environment. Controlling macrophage function to facilitate immunological regeneration or fighting pathology has emerged as a therapeutic possibility. The rate-limiting step in translating macrophage immunomodulation therapies has been the absence of fundamental knowledge of how physics and biochemistry in the macrophage microenvironment converge to inform phenotype. In this review we explore recent trends in bioengineered model systems that integrate physical and biochemical variables applied to macrophage mechanosensing and plasticity. We focus on how tuning of mechanical forces and biomaterial composition orchestrate macrophage function in physiological and pathological contexts. Ultimately, a broader understanding of stimuli-responsiveness in macrophages leads to informed design for future modulatory therapies.

Keywords: engineering approaches; in vitro models; macrophages; mechanosensing; microenvironment.

Figure 1:

Macrophage Mechanosensing: Three main mechanisms are implicated in translating mechanical cues into cellular responses in macrophages: i) actin cytoskeletal components, ii) integrins, and iii) mechanosensitive ion channels. The actin cytoskeleton can independently mediate macrophage mechanosensing through RhoA/ROCK signaling while also being affected downstream of integrin signaling. In response to physical force changes, the actin structure will undergo remodeling and promote downstream signal transduction. Integrins are crucial in governing macrophage function by mediating cell adhesion to extracellular matrix components and to other cells. Alterations in the matrix architecture and cytoskeletal stiffness are sensed by integrin-ligand interactions through outside-in and inside-out signaling. Mechanosensitive ion channels, such as Piezo1 and TRPV4, are opened when physical forces alter the tension in the cellular membrane. Following any course of macrophage mechanosensing, intracellular signals are then sent to the nucleus through numerous activation pathways where transcription factors induce different polarization states or functional alterations including phagocytosis, migration or apoptosis. Activation pathways are complex in nature and inherently have a lot of overlap in methods of activation. For example, the RhoA/ROCK pathway and the resulting actin structure is primarily activated by receptor tyrosine kinases but can also be activated by integrins. Further, many other molecular mechanisms are implicated in macrophage behavior through pattern recognition receptors (PPRs), such as Toll-like receptors, and cytokine receptors. Important pathways like NF-κB and JAK/STAT are activated via membrane associated receptors in response to external stimuli. NF-κB is another pathway example that can be activated by numerous molecular mechanisms like integrins and mechanosensitive ion channels. (Made on BioRender)

Figure 2:

Model Systems and Translational Technologies Dictating Macrophage Behavior: Naïve macrophages are influenced by their environment to adopt a pro-inflammatory state, a pro-regenerative state, or a mix of both. Macrophages can also be re-educated to go from a pro-inflammatory to a pro-regenerative state or vice versa. This review covers both material and mechanical based models that demonstrate how forces and environmental interactions can influence macrophage behavior. Depending on the forces applied, such as shear stress, compression, and tension, or the properties of the materials, including stiffness, architecture, or source, macrophages will respond accordingly. With the information gained from both material and mechanical based models, researchers can design translational technologies for clinical applications to dictate macrophage function. Some recent examples of translational technologies are shape memory polymer foam coated coils for aneurysms, polymer backpacks, neural probes with nanoparticles, Chimeric Antigen Receptor (CAR)-Macrophages, and other nanomaterial drug delivery systems. (Made on BioRender)