Mechanoimmunology: Are inflammatory epigenetic states of macrophages tuned by biophysical factors?

Abstract

Many inflammatory diseases that are responsible for a majority of deaths are still uncurable, in part as the underpinning pathomechanisms and how to combat them is still poorly understood. Tissue-resident macrophages play pivotal roles in the maintenance of tissue homeostasis, but if they gradually convert to proinflammatory phenotypes, or if blood-born proinflammatory macrophages persist long-term after activation, they contribute to chronic inflammation and fibrosis. While biochemical factors and how they regulate the inflammatory transcriptional response of macrophages have been at the forefront of research to identify targets for therapeutic interventions, evidence is increasing that physical factors also tune the macrophage phenotype. Recently, several mechanisms have emerged as to how physical factors impact the mechanobiology of macrophages, from the nuclear translocation of transcription factors to epigenetic modifications, perhaps even DNA methylation. Insight into the mechanobiology of macrophages and associated epigenetic modifications will deliver novel therapeutic options going forward, particularly in the context of increased inflammation with advancing age and age-related diseases. We review here how biophysical factors can co-regulate pro-inflammatory gene expression and epigenetic modifications and identify knowledge gaps that require urgent attention if this therapeutic potential is to be realized.

Matrix-rigidity cooperates with biochemical cues in M2 macrophage activation through increased nuclear deformation and chromatin accessibility

“…The full understanding of how podosome-like actin structures can transduce mechanical stresses into the nucleus and how alterations in nuclear mechanics modulate macrophage activation remain elusive. While it is known that the linker of nucleoskeleton and cytoskeleton (LINC) complex, composed of SUN-domain proteins and KASH-domain proteins across the inner and outer nuclear membranes, is implicated in linking the nuclear lamina/chromatin and cytoskeleton 50,51 , the physical connection between podosome and the nucleus remains unknown 65 . Our speculation posits that higher matrix rigidity increases cellular spreading through the augmentation of podosome-like actin structure formation, acting as tent nails.…”

Osteointegration of Ti Bone Implants: A Study on How Surface Parameters Control the Foreign Body Response

“…The activation of FAK and Src leads to activation of Rho/ROCK pathways (Figure c) involved in actin polymerization. Polymerization of actin results in the nuclear translocation of transcription factors such as yes-associated protein (YAP), mechanosensitive transcriptional cofactors, and myocardin related transcription factor-A (MRTF-A), activating NFκB signaling pathway and upregulating pro-inflammatory genes (Figure d). ,− Uncontrolled NFκB activation is a hallmark of chronic inflammatory diseases and is a central mediator of inflammatory gene induction that acts in both innate and adaptive immune cells …”

“…In addition to integrins, mechanically activated ion channels (PIEZO, Transient receptor potential vanilloid type 4 (TRPV4)) regulate the translocation of YAP and MRTF-A (Figure b). These channels open in response to membrane tension, allowing calcium influx, which promotes actin polymerization as well as the activation of calcium-dependent signaling pathways that lead to inflammatory responses. , Tang et al evaluated a 3D printed low-elastic-modulus Ti2448 (Ti-24Nb-4Zr-7.9Sn) alloy that decreased RAW 264.7 macrophages’ PIEZO1 expression and YAP nuclear translocation in comparison to the conventional Ti6Al4 V alloy. This resulted in decreased CCR7 and iNOS expression, and IL1β and TNFα secretion, while it increased Arginase 1 expression and IL4, IL10, and BMP-2, and PDGF secretion (Figure c) .…”

Biomechanics of Macrophages on Disordered Surface Nanotopography

“…Accumulating evidence shows that macrophages are able to self-regulate their functions by sensing and interacting with chemical, physical, and mechanical stimuli from their surrounding microenvironment, including other cells, soluble factors and cues, and the extracellular matrix (ECM). ,− Within physical stimuli, macrophages are especially sensitive to surface properties, such as mechanical, , electrical (governed by charge , and wettability − ), and geometrical characteristics (such as 2D, − 3D topography , and roughness − ). All of these physical cues, in synergy with biochemical stimuli, have a profound impact on macrophage functions, directly influencing adhesion, migration, and consequently their immune response.…”