Role of CCR5 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

Abstract

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-1α/CCL3 and MIP-1β/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-1α/CCL3, MIP-1β/CCL4, MCP-1/CCL-2), matrix metalloproteinase-9 and cell death regulators (Fas, TNF, TNFR1, TNFR2, Bid), optimal IL-13 inhibition of α1-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.

Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1

“…CCR5 is a chemokine receptor that plays a critical role in Th1 type immunity to pathogens (19) and is a coreceptor for HIV infection (20). Aberrant up-regulation of CCR5 in T lymphocytes is implicated in the induction of Th1-type responses in rheumatoid arthritis and transplant rejection (21).…”

Tumor-Derived Chemokine CCL5 Enhances TGF-β–Mediated Killing of CD8+ T Cells in Colon Cancer by T-Regulatory Cells

“…Quantitative real-time PCR (qRT-PCR) was carried out as previously descried (26). Previously described primers of the targeted genes were used in the study (26,27).…”

The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

“…The quality of isolated RNA was examined by ethidium bromide staining of RNA separated in an agarose gel, and the concentration of RNA was determined spectrophotometrically. Semiquantitative RT-PCR was performed as previously described (13,14). Previously described primers of the targeted genes were used in the study (13,14).…”