Froom Zachary S C S, Callaghan Neal I, Davenport Huyer Locke
School of Biomedical Engineering, Faculties of Medicine and Engineering, Dalhousie University, Halifax, NS B3H 4R2, Canada.
Department of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada.
J Biol Chem. 2025 May 5:110203. doi: 10.1016/j.jbc.2025.110203.
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 through the release of 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 signalling that enables their pro-fibrotic behaviour. We then finish with a set of recommendations for future experimentation with the goal of developing 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.
病理性纤维化是细胞外基质的过度沉积和组织硬化，会导致进行性器官功能障碍，是多种慢性疾病的基础。纤维化微环境是由多种细胞类型之间动态的微环境相互作用驱动的；巨噬细胞和成纤维细胞在纤维化疾病的起始、维持和进展中起着核心作用。巨噬细胞对微环境刺激的功能可塑性通过释放促炎细胞因子、生长因子和基质重塑酶来调节成纤维细胞的功能，这些酶可促进成纤维细胞增殖、激活并分化为肌成纤维细胞。活化的成纤维细胞和肌成纤维细胞作为纤维化效应细胞，分泌细胞外基质成分并引发微环境挛缩。成纤维细胞还通过释放自身的促炎细胞因子和生长因子来调节巨噬细胞功能，形成双向串扰，从而加强慢性纤维化循环。巨噬细胞和成纤维细胞之间复杂的相互作用，包括它们的分泌产物和信号相互作用，会导致组织损伤和组织功能的病理性丧失。在这篇综述中，我们研究了病理性纤维化条件下巨噬细胞-成纤维细胞的相互动态作用。我们讨论了与纤维化进展相关的巨噬细胞和成纤维细胞的特定谱系和功能，重点关注它们的信号转导途径和能够实现其促纤维化行为的分泌信号。然后，我们以一组未来实验的建议作为结尾，目标是开发一系列抗纤维化治疗候选药物的潜在靶点。了解巨噬细胞和成纤维细胞之间的细胞相互作用，为减轻纤维化疾病进展的潜在治疗策略提供了有价值的见解。
