The Wnt antagonist Dickkopf1(DKK1) promotes pulmonary fibrosis via M2-like macrophage polarization

Abstract

Abstract Tissue fibrosis is a progressive pathological process induced by repeated tissue injury and inflammation resulting in excessive collagen deposition. The Wnt signaling pathway regulates cell proliferation and differentiation for tissue repair processes. Dickkopf1 (DKK1) is a quintessential inhibitory ligand of the Wnt pathway. M2-like macrophages, induced by type 2 cytokines such as IL-13, play a central role in tissue fibrosis. We found that DKK1 protein expression markedly increased in both lung tissues of human idiopathic pulmonary fibrosis (IPF) and lungs from the murine bleomycin (BLM)-induced fibrosis model. To investigate the role of DKK1 in lung fibrosis, we used the DKK1 hypomorphic doubleridge (Dkk1d/d) mouse model. Collagen mRNA and protein expressions were markedly decreased in the lungs of Dkk1d/d mice compared to those of WT mice upon BLM challenge. The infiltration of macrophages was significantly decreased in the lungs of Dkk1d/d mice upon lung injury. We tested whether DKK1 modulates the polarization of M2-like macrophages in vitro using mouse bone marrow-derived macrophages (BMDMs). Interestingly, DKK1 induced M2-like macrophage marker CD206 (mannose receptor) and Arginase 1 (Arg1) protein expression. The expression of CD206 and Arg1 was synergistically increased by DKK1 and IL-13. We demonstrated that DKK1 utilizes STAT6 and JNK to induce Arg1 and CD206. Taken together, our study demonstrates that DKK1 promotes pulmonary fibrosis by activation of M2-like macrophages. Our study will provide new mechanistic insights into DKK1-mediated lung fibrosis pathogenesis.