Abstract / Summary
Fibrosis has traditionally been viewed as a fibroblast- and myofibroblast-centred process, in which immune cells regulate matrix deposition primarily through inflammatory mediators and paracrine signalling. However, advances in single-cell profiling, spatial analyses and lineage-resolved approaches are beginning to challenge this rigid division of cellular labour. Emerging evidence indicates that, in persistently injured and maladaptively repairing tissues, selected immune cell populations can acquire matrix producing, cytoskeletal remodelling and mesenchymal-like functions, thereby contributing more directly to structural tissue remodelling. In this Review, we introduce the concept of immune cell fibrotic plasticity and critically assess the evidence, regulatory mechanisms and pathological significance of fibrotic effector states in macrophages, neutrophils and T cells. Macrophage reprogramming towards myofibroblast-like states appears to be shaped by convergent TGF-β/SMAD signalling, metabolic adaptation and epigenetic regulation. Neutrophils can synthesize, transport and organize extracellular matrix, conferring temporally distinct functions in tissue stabilization and pathological scarring. Evidence for mesenchymal-like reprogramming of T cells remains limited, but raises the possibility that adaptive immune cells can also acquire structural effector functions. Importantly, co-expression of immune and mesenchymal markers does not, by itself, establish stable lineage conversion. These phenomena are more appropriately understood as microenvironmentally induced, context-dependent functional states rather than universal or complete transdifferentiation. Defining the origins, reversibility and quantitative contribution of these states will determine whether immune-cell fibrotic plasticity can be exploited for disease stratification and the development of more selective antifibrotic therapies.