IL-6-Mediated Macrophage–Fibroblast Communication in Pathological Lung Remodeling

This is the authors' abstract. We don't add key points for this paper.

Fibrosis is a pathological form of tissue remodeling driven by excessive deposition of extracellular matrix (ECM). Unlike physiological tissue repair, fibrosis arises from persistent myofibroblast activation and unresolved inflammation. Chronic inflammation can both initiate fibrotic remodeling and be sustained by the resulting tissue alterations, supporting the view of fibrosis as an immune-mediated process. Fibrogenesis is fundamentally shaped by interactions between macrophages and fibroblasts. Polarized macrophages can modulate fibroblast activity and promote their differentiation into myofibroblasts. IL-6 is an important mediator of macrophage–fibroblast communication and has been implicated in fibrotic diseases affecting multiple organs. Notably, the effects of IL-6 are highly context-dependent. During acute injury, IL-6 can promote tissue repair by stimulating epithelial proliferation and angiogenesis, whereas persistent IL-6 signaling in chronic inflammation can become a major driver of fibrosis. IL-6 is also a prominent component of the senescence-associated secretory phenotype (SASP), providing a mechanistic link between fibrosis, cellular senescence, and inflammaging. In this review, we provide an integrated overview of the role of IL-6 in macrophage–fibroblast interactions during pulmonary fibrogenesis, with particular emphasis on its context-dependent functions at the interface between tissue repair and pathological tissue remodeling. We also discuss current therapeutic strategies aimed at targeting IL-6 signaling.