CX3CL1 up-regulation is associated with recruitment of CX3CR1+ mononuclear phagocytes and T lymphocytes in the lungs during cigarette smoke-induced emphysema

Am J Pathol. 2008 Oct;173(4):949-61. doi: 10.2353/ajpath.2008.071034. Epub 2008 Sep 4.


CX3CR1 is expressed on monocytes, dendritic cells, macrophages, subsets of T lymphocytes, and natural killer cells and functions in diverse capacities such as leukocyte adhesion, migration, and cell survival on ligand binding. Expression of the CX3CL1 gene, whose expression product is the sole ligand for CX3CR1, is up-regulated in human lungs with chronic cigarette smoke-induced obstructive lung disease. At present, it is unknown whether CX3CL1 up-regulation is associated with the recruitment and accumulation of immune cells that express CX3CR1. We show that mice chronically exposed to cigarette smoke up-regulate CX3CL1 gene expression, which is associated with an influx of CX3CR1+ cells in the lungs. The increase in CX3CR1+ cells is primarily comprised of macrophages and T lymphocytes and is associated with the development of emphysema. In alveolar macrophages, cigarette smoke exposure increased the expression of both CX3CR1 and CX3CL1 genes. The inducibility of CX3CR1 expression was not solely dependent on a chronic stimulus because lipopolysaccharide up-regulated CX3CR1 in RAW264.7 cells in vitro and in mononuclear phagocytes in vivo. Our findings suggest a mechanism by which macrophages amplify and promote CX3CR1+ cell accumulation within the lungs during both acute and chronic inflammatory stress. We suggest that one function of the CX3CR1-CX3CL1 pathway is to recruit and sustain divergent immune cell populations implicated in the pathogenesis of cigarette smoke-induced emphysema.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD3 Complex / metabolism
  • CX3C Chemokine Receptor 1
  • Cell Line
  • Cell Movement / drug effects
  • Chemokine CX3CL1 / genetics*
  • Chemokine CX3CL1 / metabolism
  • Humans
  • Inflammation
  • Lipopolysaccharides / pharmacology
  • Lung / metabolism
  • Lung / pathology*
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / pathology
  • Male
  • Mice
  • Neutrophils / drug effects
  • Phagocytes / drug effects
  • Phagocytes / pathology*
  • Pulmonary Emphysema / chemically induced
  • Pulmonary Emphysema / genetics
  • Pulmonary Emphysema / pathology*
  • Receptors, Chemokine / genetics*
  • Receptors, Chemokine / metabolism
  • Smoking / adverse effects*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / pathology*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics


  • CD3 Complex
  • CX3C Chemokine Receptor 1
  • CX3CR1 protein, human
  • Chemokine CX3CL1
  • Cx3cr1 protein, mouse
  • Lipopolysaccharides
  • Receptors, Chemokine