Immunological mechanisms underlying fibrotic diseases via single-cell technologies

Fibrosis is an organ dysfunction caused by excessive deposition of fibrous components produced by parenchymal cells. Effective treatments are lacking for this progressive pathological condition that manifests in various organs and can lead to mortality. The involvement of the immune system in various aspects of fibrosis development, including chronic organ damage induced by macrophages and T cells, wound healing by macrophages and growth factors such as TGF-β, and polarization toward the type II cytokine phenotype, has been widely reported. Recently, immune cells were also reported to contribute to the resolution phase of fibrotic conditions, highlighting the relevance of immune cell analysis in the understanding of both progression and recovery of fibrotic pathologies. However, owing to the complexity and diversity of disease progression, conventional pathological analyses that focus on individual cells and factors have limitations. Technological advancements, such as next-generation sequencing and spatial transcriptome analysis, have enabled pathological analysis at the single-cell level rendering positional information on cells within organs. These advancements have allowed for the redefinition of heterogeneous cells present in organs and a precise understanding of individual cell phenotypes from small human patient samples. Furthermore, integration of transcriptome, proteome, and epigenome data from each cell has begun to reveal important cell-cell interactions under various fibrotic conditions. This review comprehensively discusses the involvement of the immune system and fibrosis, as well as the key interactions between immune and parenchymal cells unraveled via recent advancements in single-cell analysis of fibrotic pathologies in various organs. It also introduces novel strategies leveraging the latest single-cell analyses for fibrosis treatment.