# Modulation of macrophages by biophysical cues in health and beyond

## TL;DR

This paper reviews how biophysical signals in the environment influence macrophage behavior, impacting health and disease outcomes.

## Contribution

It highlights the emerging field of mechano-immunology and how biophysical cues modulate macrophage function alongside biochemical signals.

## Key findings

- Biophysical cues like extracellular matrix stiffness and mechanical forces influence macrophage polarization and function.
- Changes in tissue biophysics during aging and disease alter macrophage responses, affecting disease progression.
- Integrating biophysical and biochemical signals is crucial for determining macrophage roles in homeostasis and pathology.

## Abstract

Macrophages play a key role in tissue development and homeostasis, innate immune defence against microbes or tumours, and restoring homeostasis through tissue regeneration following infection or injury. The ability to adopt such diverse functions is due to their heterogeneous nature, which is driven largely by their developmental origin and their response to signals they encounter from the microenvironment. The most well-characterized signals driving macrophage phenotype and function are biochemical and metabolic. However, the way macrophages sense and respond to their extracellular biophysical environment is becoming increasingly recognized in the field of mechano-immunology. These biophysical cues can be signals from tissue components, such as the composition and charge of extracellular matrix or topography, elasticity, and stiffness of the tissue surrounding cells; and mechanical forces such as shear stress or stretch. Macrophages are important in determining whether a disease resolves or becomes chronic. Ageing and diseases such as cancer or fibrotic disorders are associated with significant changes in the tissue biophysical environment, and this provides signals that integrate with those from biochemical and metabolic stimuli to ultimately dictate the overall function of macrophages. This review provides a brief overview of macrophage polarization, followed by a selection of commonly recognized physiological and applied biophysical stimuli impacting macrophage activity, and the potential signalling mechanisms driving downstream responses. The effects of biophysical cues on macrophages’ function in homeostasis and disease and the associated clinical implications are also highlighted.

Graphical Abstract