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

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. (C) 2022 Author(s).All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY)license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

Many incurable inflammatory diseases contribute to majority of deaths due to poor understanding of underlying pathomechanisms. Tissue-resident macrophages play a crucial role in maintaining tissue homeostasis, but when they convert to proinflammatory phenotypes or persist as blood-born proinflammatory macrophages, chronic inflammation and fibrosis occur. While biochemical factors have been the focus of research in therapeutic interventions, physical factors are also found to regulate the macrophage phenotype. Understanding the mechanobiology and epigenetic modifications of macrophages could lead to new therapeutic options for increased inflammation related to aging and age-related diseases.