CRTH2 Mediates Pro-fibrotic Macrophage Differentiation and Promotes Lung Fibrosis

Am J Respir Cell Mol Biol. 2022 May 18. doi: 10.1165/rcmb.2021-0504OC. Online ahead of print.ABSTRACTIdiopathic pulmonary fibrosis (IPF) is a particularly deadly form of pulmonary fibrosis with unknown reason. In patients with IPF, high serum and lung levels of CHI3L1 can be detected and are associated with poor survival. However, the roles of CHI3L1 in these diseases have not been fully elucidated. We hypothesize that CHI3L1 interacts with CRTH2 to stimulate pro-fibrotic macrophage differentiation and the development of pulmonary fibrosis and that circulating blood monocytes from patients with IPF are hyperresponsive to CHI3L1-CRTH2 signaling. We used murine pulmonary fibrosis models to investigate the role of CRTH2 on pro-fibrotic macrophage differentiation and fibrosis development, and primary human PBMC cell culture to detect the difference of monocytes in the responses to CHI3L1 stimulation and CRTH2 inhibition between IPF patients and normal controls. Our results showed that null mutation or small molecule inhibition of CRTH2 prevents the development of pulmonary fibrosis in murine models. Furthermore, CHI3L1 stimulation induces a greater increase in CD206 expression in IPF monocytes than control monocytes. These results demonstrated that monocytes from IPF patients appear to be hyperresponsive to CHI3L1 stimulation. These studies support targeting CHI3L1-CRTH2 pathway as a promising therapeutic approach in IPF and that the sensitivity of blood monocytes to CHI3L1-induc...
Source: Respiratory Care - Category: Respiratory Medicine Authors: Source Type: research