Cigarette Smoke-Induced Pulmonary Inflammation and Emphysema Are Attenuated in CCR6-Deficient Mice

Abstract

Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking, and is characterized by an increase in inflammatory cells in the airways and pulmonary tissue. The chemokine receptor CCR6 and its ligand MIP-3α/CCL20 may be involved in the recruitment of these inflammatory cells. To investigate the role of CCR6 in the pathogenesis of COPD, we analyzed the inflammatory responses of CCR6 knockout (KO) and wild-type mice upon cigarette smoke (CS) exposure. Both subacute and chronic exposure to CS induced an increase in cells of the innate and adaptive immune system in the bronchoalveolar lavage, both in CCR6 KO and wild-type mice. However, the accumulation of dendritic cells, neutrophils, and T lymphocytes, which express CCR6, was significantly attenuated in the CCR6 KO mice, compared with their wild-type littermates. In the lung tissue of CCR6 KO mice, there was an impaired increase in dendritic cells, activated CD8+ T lymphocytes, and granulocytes. Moreover, this attenuated inflammatory response in CCR6 KO mice offered a partial protection against pulmonary emphysema, which correlated with an impaired production of MMP-12. Importantly, protein levels of MIP-3α/CCL20, the only chemokine ligand of the CCR6 receptor, and MCP-1/CCL2 were significantly increased upon CS exposure in wild-type, but not in CCR6 KO mice. In contrast, CCR6 deficiency had no effect on the development of airway wall remodeling upon chronic CS exposure. These results indicate that the interaction of CCR6 with its ligand MIP-3α contributes to the pathogenesis of CS-induced pulmonary inflammation and emphysema in this murine model of COPD.

Chronic Obstructive Pulmonary Disease: Evidence for an Autoimmune Component

“…It is also noteworthy that Th17 cells in the airways of emphysematous mice express the chemokine receptor CCR6 (40). CCR6 deficient mice have previously been found to be protected from cigarette smoke induced pulmonary inflammation and airspace enlargement perhaps indicating an important role for Th17 cells (29).…”

“…Such discrepencies likely reflect differences in terms of markers used to detect DC subsets as well as analysis of DC subsets from either whole lung tissue, bronchoalveolar lavage or immunohistochemistry on specific tissue sections such as the small airways. The observation that deficiency in the chemokine receptor CCR6 Volume 6 Number 2 April 2009 confers protection in a murine model of cigarette smoke induced pulmonary inflammation and emphysema points to a mechanistic role for DC in promoting disease progression (29). CCR6 is a chemokine receptor whose expression is largely associated with tissue infiltrating proinflammatory DC (as well as with specific T cell subsets) and it has subsequently been demonstrated that COPD patients have significantly elevated levels of the CCR6 ligand, CCL20, in the lung (28).…”

Chemokine receptor CXCR3 is important for lung tissue damage and airway remodeling induced by short-term exposure to cigarette smoking in mice

“…Quantification of Lm was done by light microscopy by two blinded investigators according to previously described methods [7,8] . Briefly, the Lm was measured by placing a 100×100-µm grid on each field.…”

“…An antagonist of CXCR2 has been shown to abrogate lung neutrophilic inflammation in rodent models of CS exposure [11] . Lung tissue inflammation and emphysema induced by CS were significantly decreased in both CCR5-/-and CCR6-/-mice through the decreased release of macrophage inflammatory Chemokine receptor CXCR3 is important for lung tissue damage and airway remodeling induced by short-term exposure to cigarette smoking in mice www.chinaphar.com Nie L et al Acta Pharmacologica Sinica npg proteins: (MIP)-1α, MIP-1β, CXCL10, and MIP-3α [7,8] .…”

“…The roles of chemokines via their respective receptors in the pathogenesis of COPD have been extensively addressed elsewhere [7][8][9] . For example, CXCL9, and CXCL10, and CXCL11 and CCL5, ligands for CXCR3 and CCR5, respectively, were shown to be elevated in sputum from COPD patients [10] .…”