Cellular crosstalk in fibrosis: Insights into macrophage and fibroblast dynamics

Abstract

Pathological fibrosis, the excessive deposition of extracellular matrix and tissue stiffening that causes progressive organ dysfunction, underlies diverse chronic diseases. The fibrotic microenvironment is driven by the dynamic microenvironmental interaction between various cell types; macrophages and fibroblasts play central roles in fibrotic disease initiation, maintenance, and progression. Macrophage functional plasticity to microenvironmental stimuli modulates fibroblast functionality by releasing pro-inflammatory cytokines, growth factors, and matrix remodeling enzymes that promote fibroblast proliferation, activation, and differentiation into myofibroblasts. Activated fibroblasts and myofibroblasts serve as the fibrotic effector cells, secreting extracellular matrix components and initiating microenvironmental contracture. Fibroblasts also modulate macrophage function by releasing their own pro-inflammatory cytokines and growth factors, creating bidirectional crosstalk that reinforces the chronic fibrotic cycle. The intricate interplay between macrophages and fibroblasts, including their secretomes and signaling interactions, leads to tissue damage and pathological loss of tissue function. In this review, we examine macrophage-fibroblast reciprocal dynamic interactions in pathological fibrotic conditions. We discuss the specific lineages and functionality of macrophages and fibroblasts implicated in fibrotic progression, with focus on their signal transduction pathways and secretory signaling that enables their pro-fibrotic behavior. We then finish with a set of recommendations for future experimentation to develop a set of potential targets for anti-fibrotic therapeutic candidates. Understanding the cellular interactions between macrophages and fibroblasts provides valuable insights into potential therapeutic strategies to mitigate fibrotic disease progression.

Keywords: extracellular matrix; fibroblasts; fibrosis; inflammation; macrophages.

Figure 1

Canonical M1-M2 macrophage paradigm. Macrophage activity spans a wide range of functionality, which is typically stratified using the M1-M2 paradigm. Macrophage subclasses are defined by their in vitro inducing factors and, subsequently, what surface markers they express. M1 macrophages are dependent on glycolytic methods for energy production and exhibit pro-inflammatory functionality, while M2 macrophages typically are dependent on oxidative methods and exhibit more pro-reparative functionality.

Figure 2

Dynamic macrophage–fibroblast reciprocal interactions. Macrophages and fibroblasts primarily communicate (recruiting additional cells or activating existing cells) through secretome signaling that can act either on the opposite (→, ↔) or on the same cell type (↻) (potentially in an autocrine fashion). Additionally, macrophage and fibroblast both secrete MMPs (balanced by TIMPs) that degrade the ECM, potentially releasing trapped inducing factors (growth factors/cytokines). These cells further activate one another through cell-cell contact signaling. These cells also exhibit contact signaling with the ECM, which can further modulate their activation. Fibroblast activation drives ECM deposition, which further adds onto dynamic interactions through cell attachment and diffusion limitations of activating factors.

Figure 3

Resident macrophages in fibrotic pathologies. Tissue resident macrophages exhibit unique interactions in fibrotic disease progression dependent on their specific tissue microenvironment and tissue resident stromal cells. The fibrotic ECM profile varies in each pathology, with the most notable differences being in the dominate collagen types. Ultimately, the loss of tissue resident macrophages plays a key role in the downstream tissue pathology.