Essential involvement of the CX3CL1-CX3CR1 axis in bleomycin-induced pulmonary fibrosis via regulation of fibrocyte and M2 macrophage migration

Abstract

The potential role of macrophages in pulmonary fibrosis (PF) prompted us to evaluate the roles of CX3CR1, a chemokine receptor abundantly expressed in macrophages during bleomycin (BLM)-induced PF. Intratracheal BLM injection induced infiltration of leukocytes such as macrophages into the lungs, which eventually resulted in fibrosis. CX3CR1 expression was mainly detected in the majority of macrophages and in a small portion of α-smooth muscle actin-positive cells in the lungs, while CX3CL1 was expressed in macrophages. BLM-induced fibrotic changes in the lungs were reduced without any changes in the number of leukocytes in Cx3cr1 −/− mice, as compared with those in the wild-type (WT) mice. However, intrapulmonary CX3CR1+ macrophages displayed pro-fibrotic M2 phenotypes; lack of CX3CR1 skewed their phenotypes toward M1 in BLM-challenged lungs. Moreover, fibrocytes expressed CX3CR1, and were increased in BLM-challenged WT lungs. The number of intrapulmonary fibrocytes was decreased in Cx3cr1 −/− mice. Thus, locally-produced CX3CL1 can promote PF development primarily by attracting CX3CR1-expressing M2 macrophages and fibrocytes into the lungs.

Reference-based annotation of single cell transcriptomes identifies a profibrotic macrophage niche after tissue injury

“…Remarkably, a high percentage of cells from C2 had high expression of genes from both C1 and C3 (Figure 2d), suggesting that C2 represents a transitional state unique to the disease model and intermediate between C1 and C3. Moreover, Cx3cr1, Ccr2, Mafb, and MHCII genes were common to C2 and C3 and are consistent with macrophages of monocytic origin, as previously reported in bleomycin-induced lung fibrosis 10,26 . To confirm these findings for C2, we sorted alveolar macrophages (SiglecF+ CD11c+) after injury by MHCII-low and MHC-high expression to distinguish the C1 and C2 subclusters, respectively.…”

CX3CL1 and CX3CR1 could be a relevant molecular axis in the pathophysiology of idiopathic pulmonary fibrosis

“…This result suggests that, similar to what is reported on liver damage, the interaction between CX3CR1 and CX3CL1 has a protective function in relation to the production of collagen [12]. In contrast, in the murine model of bleomycin-induced pulmonary fibrosis, an upregulation of the CX3CL1-CX3CR1 axis was associated with intrapulmonary accumulation of profibrotic M2 macrophages, while CX3CR1 -/mice exhibited a reduction of M2 macrophage recruitment and collagen production [16], suggesting a profibrotic role of the CX3CL1-CX3CR1 axis. The bleomycin model has been very valuable in understanding various aspects of the pathophysiology of idiopathic pulmonary fibrosis.…”

Endothelial cell‑derived CCL15 mediates the transmigration of fibrocytes through the CCL15‑CCR1 axis in vitro

“…CFs (18,24). In the present study, although gene chip resulted in the identification of several chemokines a limitation of the present study is that only three chemokines were selected based on their fold-changes in expression.…”

“…Chemokines involved in the transmigration of fibrocytes in fibrotic diseases have been widely studied (8,17,18). However, chemokines that regulate the transmigration of fibrocytes during wound healing remain poorly understood.…”