Targeting a Monocyte Subset to Reduce Inflammation

Therapeutic siRNA Silencing in Inflammatory Monocytes in Mice Leuschner et al Nat Biotech . 2011;29:1005–1010.R ecently in Nature Biotechnology , Leuschner et al1 described an elegant method of limiting the recruitment of a proinflammatory subset of monocytes in mouse models of inflammation. Although providing prospects for therapeutic application, especially in cardiovascular diseases, it raises questions that make it necessary to proceed with caution .In this technical tour-de-force, Leuschner et al1 exploited the findings that murine macrophages that consist of two defined subsets differing in Ly6 antigen expression also differ in their expression of a major chemokine receptor, CCR2, responsible for the recruitment of circulating LY6C hi CCR2+ monocytes to peripheral sites of inflammation. They utilized lipid nanoparticles containing siRNA against CCR2 to deplete the recruitment of this subset and to attenuate inflammation in several models of vascular injury (myocardial infarction, atherosclerotic plaques), islet cell transplantation in diabetic mice, and tumor-associated macrophage recruitment. These striking results raise the possibility of limiting the deleterious effects of selected monocyte subsets while preserving housekeeping and clearance functions of resident tissue macrophages, which are essential for host homeostasis and survival. By optimizing the nanoparticle delivery system and the siRNA used for silencing, combined with sophisticated imaging in defined mouse models of disease, they achieved striking improvements over currently available anti-CCR2 antibodies or small molecule inhibitors.Figure summarizes the experimental strategy, which is based on previous knowledge of monocyte subpopulations and the importance of CCR2+ monocyte recruitment to sites of a range of metabolic and inflammatory stimuli. Inhibition of the inflammatory monocyte subset was demonstrated by gene ablation or reduction of CCR2 expression and antibody blockade of the actions of MCP-1, its ligand, in vitro and in vivo. The nanoparticles, which had been optimized …