Macrophage-stroma interactions in fibrosis: biochemical, biophysical, and cellular perspectives

Abstract

Fibrosis results from aberrant wound healing and is characterized by an accumulation of extracellular matrix, impairing the function of an affected organ. Increased deposition of extracellular matrix proteins, disruption of matrix degradation, but also abnormal post-translational modifications alter the biochemical composition and biophysical properties of the tissue microenvironment - the stroma. Macrophages are known to play an important role in wound healing and tissue repair, but the direct influence of fibrotic stroma on macrophage behaviour is still an under-investigated element in the pathogenesis of fibrosis. In this review, the current knowledge on interactions between macrophages and (fibrotic) stroma will be discussed from biochemical, biophysical, and cellular perspectives. Furthermore, we provide future perspectives with regard to how macrophage-stroma interactions can be examined further to ultimately facilitate more specific targeting of these interactions in the treatment of fibrosis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: antifibrotic; extracellular matrix; microstructure; migration; phagocytosis; polarization; profibrotic; shear stress; stiffness; stretch.

Figure 1

Schematic representation of stroma in healthy and fibrotic conditions. In fibrosis, aberrant ECM deposition and remodelling, as well as higher numbers and altered behaviour of fibroblasts and macrophages, change the biochemical and biophysical properties of stroma, and the consequential interactions with resident cells.

Figure 2

Macrophages in stroma. Tissue macrophages derive from different origins. Despite their differences, macrophages from all origins can change their polarization status to a more pro‐inflammatory or profibrotic/anti‐inflammatory phenotype upon stimuli from their microenvironment, as can be identified by metabolic changes (arginase‐1 versus NO), the expression of surface markers (e.g. MHCII and CD206) or the expression and secretion of cytokines (e.g. TGF‐β, IL‐10, TNF‐α, IL‐1β, and IL‐6). Arg‐1, arginase‐1.

Figure 3

Schematic overview of the most described mechanisms involved in interactions between fibrotic stroma and macrophages. Hypothesised involvement of signalling pathways/molecules is illustrated with dashed frames. Upregulated pro‐inflammatory markers are depicted in blue, and profibrotic/anti‐inflammatory in red. Arg‐1, arginase‐1; FAK, focal adhesion kinase; TRPV4, transient receptor potential vanilloid type 4; YAP, Yes‐associated protein.

Figure 4

Graphical overview of fibrosis‐related biochemical, biophysical, and cell‐induced changes in stroma, concurrently influencing macrophage behaviour.

Figure 5

Putative targets and therapeutics to skew profibrotic macrophages to a more pro‐inflammatory phenotype. Antagonists/inhibitors for integrin β1 [175, 176, 177, 178], integrin α2 [179, 180], CD44 [181] or TRPV4 [87, 91, 182, 183, 184]. Agonist for TLR4 [185, 186, 187]. TRPV4: transient receptor potential vanilloid type 4.