The role of CXC chemokines in pulmonary fibrosis

Abstract

The CXC chemokine family is a pleiotropic family of cytokines that are involved in promoting the trafficking of various leukocytes, in regulating angiogenesis and vascular remodeling, and in promoting the mobilization and trafficking of mesenchymal progenitor cells such as fibrocytes. These functions of CXC chemokines are important in the pathogenesis of pulmonary fibrosis and other fibroproliferative disorders. In this Review, we discuss the biology of CXC chemokine family members, specifically as it relates to their role in regulating vascular remodeling and trafficking of circulating mesenchymal progenitor cells (also known as fibrocytes) in pulmonary fibrosis.

Figure 1. Histopathology of normal lung tissue (A) and lung tissue from two patients with IPF (B and C).

Shown are (A) normal lung tissue (H&E staining); (B) IPF lung tissue with severe end-stage fibrosis and honeycomb changes (trichrome staining); and (C) IPF lung tissue with areas of fibrosis and an area compatible with a fibroblastic focus (FF) (H&E staining). Magnification, ×200.

Figure 2. Serial mechanisms of angiogenesis promoted by CXCL8.

CXCL8 is an ELR⁺ member of the CXC chemokine family. The ELR⁺ members of this chemokine family promote angiogenesis in a direct (not shown) or serial manner. (A) In a mouse model of Kaposi sarcoma, a serial mechanism of angiogenesis is the following: VEGF activation of its receptor (VEGFR) on endothelial cells leads to upregulation of the anti-apoptotic molecule BCL2. This in turn promotes the expression of endothelial cell–derived CXCL8, which functions in an autocrine and paracrine manner to promote angiogenesis (31). (B) Other serial pathways can also promote CXCL8-dependent angiogenesis, such as the signaling pathways induced by intracellular ROS, EGF, and HGF, which lead to nuclear translocation of NF-κB, expression of CXCL8 by tumor cells, and subsequent tumor-associated angiogenesis (–35). EGFR, EGF receptor; HGFR, HGF receptor.

Figure 3. Markers associated with human fibrocytes.

Human fibrocytes express ECM components (type I collagen, type III collagen, and vimentin). They also express a range of cell surface markers, including the common leukocyte antigen CD45, the hematopoietic stem cell antigen CD34, the adhesion molecules CD11b and CD18, the pan-myeloid antigen CD13, and the chemokine receptors CCR3, CCR5, CCR7, and CXCR4.

Figure 4. The role of the CXCL12-CXCR4 biological axis in fibrocyte extravasation in pulmonary fibrosis.

Lung-derived factors (such as GM-CSF, G-CSF, and M-CSF) generated under conditions of lung injury communicate with the BM to expand the number of fibrocytes in the BM and to mobilize fibrocytes that express CXCR4 into the circulation. CXCR4-expressing fibrocytes traffic through the circulation and extravasate into the lung in response to the CXCR4 ligand CXCL12, which is produced during the pathogenesis of fibrosis.