Role of the CX3CL1-CX3CR1 axis in chronic inflammatory lung diseases

Abstract

Persistent inflammation is often present in patients with lung diseases such as chronic obstructive pulmonary diseases (COPD) and pulmonary hypertension. Circulatory leukocyte migration through the lung vascular endothelium contributes to the structural destruction and remodeling seen in these chronic lung diseases. An inflammatory chemokine CX3CL1/fractalkine is associated with inflammatory lung diseases. Membrane-anchored CX3CL1 serves as an adhesion molecule to capture subsets of mononuclear leukocytes that express the sole receptor, CX3CR1. The extracellular chemokine domain of CX3CL1 can be cleaved/shed by a disintegrin and metalloproteinase domain (ADAM) from stimulus-exposed cells. Soluble CX3CL1 chemoattracts and activates CX3CR1+ leukocytes such as CD8+, CD4+, and γδ T lymphocytes, natural killer cells, dendritic cells, and monocytes/macrophages. CX3CR1+ leukocyte attachment to and migration through the lung vascular endothelium lead to mononuclear cell accumulation in the lung vessel walls and parenchyma. Infiltrated CX3CR1+ immune cells can release mediators to induce injury, stimulate proliferation, and/or chemoattract inflammatory cells. This contributes to structural destruction and remodeling in the development of inflammatory lung diseases. Limited clinical success in treating chronic pulmonary diseases-associated lung functional decline indicates the urgency and significance of understanding upstream signaling that triggers inflammation. This article reviews the advances in the CX3CL1-CX3CR1 axis-mediated modulation of mononuclear leukocyte adhesion and migration in inflammatory lung diseases such as COPD and pulmonary hypertension. Better understanding of the constant flow of circulating leukocytes into the lung vessel wall and parenchyma will help set a stage for the development of novel therapeutic approaches to treat or even cure chronic lung diseases including COPD and pulmonary hypertension.

Keywords: COPD; Chemokine; endothelium; fractalkine; inflammation; pulmonary; vasculature.

Figure 1

CX3CL1-CX3CR1 modulation of environmental stimulus-induced leukocyte trafficking in chronic lung diseases. Capture: Stimuli trigger endothelial CX3CL1 expression, which enhances CX3CR1⁺ leukocyte attachment to the activated lung vascular endothelium. This leads to CX3CR1⁺ leukocyte infiltration. Chemotaxis: Stimulus-induced CX3CL1 shedding by ADAM promotes CX3CR1⁺ leukocyte chemotaxis and inflammation. Transendothelial migration: Stimulus-induced CX3CL1 interaction with CX3CR1 promotes the transendothelial migration of CX3CR1⁺ leukocytes, inflammatory cell accumulation in vessel walls/parenchyma, and lung structural remodeling and destruction.