TIM-3 on myeloid cells promotes pulmonary inflammation through increased production of galectin-3

Abstract T cell immunoglobulin and mucin-containing molecule 3 (TIM-3) exhibits unique characteristics and functions that differ by cell type and status, but little is known about the cell-specific properties of TIM-3 in pathophysiological conditions. Here, we report that TIM-3 on myeloid cells plays essential roles in modulating lung inflammation and diseases. We found that myeloid cell-specific TIM-3 knock-in (FSF-TIM3/LysM-Cre+) mice have lower body weight and shorter lifespan than WT mice. Intriguingly, PET/CT analysis and histopathological examination revealed that the lungs of FSF-TIM3/LysM-Cre+ mice display excessive inflammation and features of disease-associated pathology. Similar features were observed in a different myeloid cell-specific TIM-3 knock-in mouse (FSF-TIM3/Cx3cr1-Cre+ mice). Bulk RNA-sequencing and flow cytometry revealed that galectin-3 levels are notably elevated in TIM-3-overexpressing lung-derived myeloid cells. Furthermore, blockade of TIM-3 ameliorated the levels of inflammation and galectin-3 in the lungs of FSF-TIM-3/LysM-Cre+/- mice. Using an LPS-induced lung inflammation model with myeloid cell-specific TIM-3 knock-out mice, we further demonstrated that the level of myeloid cell-expressed TIM-3 is closely associated with both lung inflammation and galectin-3. Collectively, our findings suggest that TIM-3 is an important regulator of myeloid cells in the lungs, and modulation of TIM-3 and galectin-3 could be of therapeutic benefit in inflammation-associated lung diseases.