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1.  Role of CCR5 in IFN-γ–induced and cigarette smoke–induced emphysema 
Journal of Clinical Investigation  2005;115(12):3460-3472.
Th1 inflammation and remodeling characterized by tissue destruction frequently coexist in human diseases. To further understand the mechanisms of these responses, we defined the role(s) of CCR5 in the pathogenesis of IFN-γ–induced inflammation and remodeling in a murine emphysema model. IFN-γ was a potent stimulator of the CCR5 ligands macrophage inflammatory protein–1α/CCL-3 (MIP-1α/CCL-3), MIP-1β/CCL-4, and RANTES/CCL-5, among others. Antibody neutralization or null mutation of CCR5 decreased IFN-γ–induced inflammation, DNA injury, apoptosis, and alveolar remodeling. These interventions decreased the expression of select chemokines, including CCR5 ligands and MMP-9, and increased levels of secretory leukocyte protease inhibitor. They also decreased the expression and/or activation of Fas, FasL, TNF, caspase-3, -8, and -9, Bid, and Bax. In accordance with these findings, cigarette smoke induced pulmonary inflammation, DNA injury, apoptosis, and emphysema via an IFN-γ–dependent pathway(s), and a null mutation of CCR5 decreased these responses. These studies demonstrate that IFN-γ is a potent stimulator of CC and CXC chemokines and highlight the importance of CCR5 in the pathogenesis of IFN-γ–induced and cigarette smoke–induced inflammation, tissue remodeling, and emphysema. They also demonstrate that CCR5 is required for optimal IFN-γ stimulation of its own ligands, other chemokines, MMPs, caspases, and cell death regulators and the inhibition of antiproteases.
PMCID: PMC1280966  PMID: 16284650
2.  Essential Role for the C5a Receptor in Regulating the Effector Phase of Synovial Infiltration and Joint Destruction in Experimental Arthritis 
The Journal of Experimental Medicine  2002;196(11):1461-1471.
A characteristic feature of rheumatoid arthritis is the abundance of inflammatory cells in the diseased joint. Two major components of this infiltrate are neutrophils in the synovial fluid and macrophages in the synovial tissue. These cells produce cytokines including tumor necrosis factor α and other proinflammatory mediators that likely drive the disease through its effector phases. To investigate what mechanisms underlie the recruitment of these cells into the synovial fluid and tissue, we performed expression analyses of chemoattractant receptors in a related family that includes the anaphylatoxin receptors and the formyl-MetLeuPhe receptor. We then examined the effect of targeted disruption of two abundantly expressed chemoattractant receptors, the receptors for C3a and C5a, on arthritogenesis in a mouse model of disease. We report that genetic ablation of C5a receptor expression completely protects mice from arthritis.
PMCID: PMC2194257  PMID: 12461081
arthritis; C5a receptors; granulocytes; chemoattractants; monocytes

Results 1-2 (2)