Role of CCR5 in the pathogenesis of IL-13-induced inflammation and remodeling.
IL-13 is a major effector at sites of Th2 inflammation and tissue remodeling. In these locations, it frequently coexists with the CCR5 chemokine receptor and its ligands MIP-1alpha/CCL3 and MIP-1beta/CCL4. We hypothesized that CCR5 induction and activation play important roles in the pathogenesis of IL-13-induced tissue responses. To test this hypothesis, we evaluated the effects of IL-13 on the expression of CCR5 in the murine lung. We also compared the effects of lung-targeted transgenic IL-13 in mice treated with anti-CCR5 or an Ab control and mice with wild-type or null CCR5 loci. These studies demonstrate that IL-13 is a potent stimulator of epithelial cell CCR5 expression. They also demonstrate that CCR5 neutralization or a deficiency of CCR5 significantly decreases IL-13-induced inflammation, alveolar remodeling, structural and inflammatory cell apoptosis, and respiratory failure and death. Lastly, these studies provide mechanistic insights by demonstrating that CCR5 is required for optimal IL-13 stimulation of select chemokines (MIP-1alpha/CCL3, MIP-1beta/CCL4, MCP-1/CCL-2), matrix metalloproteinase-9 and cell death regulators (Fas, TNF, TNFR1, TNFR2, Bid), optimal IL-13 inhibition of alpha1-antitrypsin, and IL-13-induction of and activation of caspases-3, -8, and-9. Collectively, these studies demonstrate that CCR5 plays a critical role in the pathogenesis of IL-13-induced inflammation and tissue remodeling.
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Bing
B
Ma
Wei
W
Liu
Robert J
RJ
Homer
Patty J
PJ
Lee
Anthony J
AJ
Coyle
Jose M
JM
Lora
Chun Geun
CG
Lee
Jack A
JA
Elias
D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004249:DNA Damage; D007249:Inflammation / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009500:Neutralization Tests; D010447:Peptide Hydrolases / Q000378:metabolism; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D018793:Interleukin-13; D019713:Receptors, CCR5; D004247:DNA; D010447:Peptide Hydrolases