Fig. 1

Mechanisms of immune cell-fibroblast interactions and how they contribute to the pathogenesis of idiopathic pulmonary fibrosis as determined by in vitro co-culture and conditioned medium model studies. Environmental toxins are inhaled into the lungs and cause repetitive injury to the epithelial layer in IPF pathogenesis. Recurrent epithelial injury causes the release of mediators that over-activate fibroblasts and attract immune cells. Fibroblasts interact with several innate immune cells resulting in various aspects of IPF pathobiology. Stimulated B cells interact with fibroblasts to increased migration in fibroblasts as well as to increase the synthesis of fibronectin, PAI1 and α-SMA. The crosstalk between T cells and fibroblasts result in increased proliferation of fibroblasts and increased collagen production. T cell-fibroblast interaction also causes a decrease in calponin and α-SMA and myofibroblast differentiation. Mast cell-fibroblast interactions are largely dependent on tryptase release, which alter fibroblast phenotype by increasing their proliferation and migration, as well as enabling the increased synthesis and release of HGF, fibronectin, collagen I, α-SMA and IL-6. Neutrophil elastase causes fibroblasts to release increasing amounts of IL-8 while a bidirectional crosstalk between fibroblasts and macrophages causes an increased expression of collagen I and III as well as the increased the release of CCL18, CCL2, CX3CL1 and CXCL10. Thus, crosstalk between various immune cells and fibroblasts contribute to IPF remodeling by triggering the overactivation of fibroblasts leading to their increased migration and proliferation which gives rise to fibroblastic foci, while also causing the overproduction and degradation of ECM proteins and contributing to the progressive accumulation of scar tissue, as well as causing the release of classical chemoattractants for immune cells (Figure created in Biorender.com)