Acute Effects and Mechanisms of Macrophage Contact Formation with Fibroblasts

Lung fibrosis, characterized by the abnormal accumulation of extracellular matrix proteins, is a debilitating condition with limited therapeutic options. My PhD study delves into the intricate cellular interactions that drive myofibroblast activation in the context of lung fibrosis, particularly focusing on the influence of acute profibrotic macrophage contact on fibroblasts within lung-soft environments. Of key mediators identified in this profibrotic cascade is the integrin ⍺vβ3 on the macrophage surface, which triggers a series of events culminating in myofibroblast activation. A crucial mechanosensitive element in this process is the stretch-activated channel Piezo1. Upon integrin binding, Piezo1 is activated, allowing an influx of calcium ions into the fibroblast. This influx serves as a pivotal signal that propels the fibroblast into a state of contraction. The dynamic contractions of fibroblasts generate intercellular stress, creating a mechanical microenvironment where forces induce the nuclear translocation of Yes-associated protein, a transcriptional coactivator known to play a role in cellular response to mechanical cues and myofibroblast activation. The repetitive nature of this process, initiated by acute macrophage contact and facilitated by Piezo1-mediated calcium influx, results in sustained fibroblast contractions and persistent Yes-associated protein nuclear translocation. We propose the collective effect of these mechanosensitive responses ultimately leads to the activation of myofibroblasts, the cell type notorious for its role in extracellular matrix deposition and tissue fibrosis. Understanding the intricate molecular and mechanical cues involved in this process sheds light on potential therapeutic targets for lung fibrosis. Targeting integrin-mediated signalling, Piezo1 activation, or downstream effectors such as Yes-associated protein may offer novel avenues for intervention, disrupting the cycle of myofibroblast activation and potentially mitigating the progression of lung fibrosis.