Tacrolimus alleviates pulmonary fibrosis progression through inhibiting the activation and interaction of ILC2 and monocytes

•The production of profibrotic cytokines by ILC2s to promote monocyte differentiation is one of the important reasons for the occurrence and development of pulmonary fibrosis.•We found that tacrolimus could inhibit the activation of ILC2s and reduce the secretion of profibrotic cytokines.•We found that tacrolimus could directly act on ILC2 to reduce the secretion of pro-fibrotic cytokines, thereby inhibiting monocyte differentiation and Mo-M activation.•Tacrolimus regulates type Ⅱ immunity by affecting the activation and interaction of ILC2s and monocytes/Mo-M, thereby alleviating pulmonary fibrosis.•Our findings demonstrated that tacrolimus is complementary to nintedanib in pharmacological mechanism, and combined treatment can significantly inhibit the progression of fibrosis. Idiopathic pulmonary fibrosis (IPF) is a heterogeneous group of lung diseases with different etiologies and characterized by progressive fibrosis. This disease usually causes pulmonary structural remodeling and decreased pulmonary function. The median survival of IPF patients is 2–5 years. Predominantly accumulation of type II innate immune cells accelerates fibrosis progression by secreting multiple pro-fibrotic cytokines. Group 2 innate lymphoid cells (ILC2) and monocytes/macrophages play key roles in innate immunity and aggravate the formation of pro-fibrotic environment. As a potent immunosuppressant, tacrolimus has shown efficacy in alleviating the progression of pulmonary fibrosis. In this study, we found that tacrolimus is capable of suppressing ILC2 activation, monocyte differentiation and the interaction of these two cells. This effect further reduced activation of monocyte-derived macrophages (Mo-M), thus resulting in a decline of myofibroblast activation and collagen deposition. The combination of tacrolimus and nintedanib was more effective than either drug alone. This study will reveal the specific process of tacrolimus alleviating pulmonary fibrosis by regulating type II immunity, and explore the potential feasibility of tacrolimus combined with nintedanib in the treatment of pulmonary fibrosis. This project will provide new ideas for clinical optimization of anti-pulmonary fibrosis drug strategies.