FIGURE 2.

Schema diagram for the role of IL‐25/IL‐33/TSLP on the pathogenesis of IPF. IL‐25/IL‐33/TSLP mainly derived from epithelial cells in response to cigarette smoke, microbe, pollutant, and stress. Increased alveolar levels of IL‐25/IL‐33/TSLP form a cytokine milieu that can recruit a variety of target cells, which express their corresponding receptors (i.e., IL‐17BR/ST2L/TSLPR), including type 2 innate lymphoid cells (ILC2s), M2‐macrophages, dendritic cells (DCs), and fibroblasts. Thus, dys‐regulated crosstalk between epithelial cells and mesenchymal cells (including resident structure cells and infiltrating innate immune cells) forms and initiates the skew of type 2 cytokine response by excessive production of IL‐4, IL‐5, and IL‐13. This uncontrolled type 2 immunity promotes continued activation of fibroblasts and epithelial injury, which will ultimately lead to excessive collagen production and irreversible fibrotic lesions. Thus, early and combined targeting of these cytokines may block the progressive type 2‐initiated fibrotic disease. Abbreviations: IL, interleukin; IPF, idiopathic pulmonary fibrosis; TSLP, thymic stromal lymphopoietin