| Autor: |
Xu D; Department of Microbiology-Immunology and., Bhattacharyya S; Northwestern Scleroderma Program, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA., Wang W; Northwestern Scleroderma Program, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.; Department of Neurological Surgery., Ifergan I; Department of Microbiology-Immunology and., Wong MAC; Department of Microbiology-Immunology and., Procissi D; Department of Radiology, and., Yeldandi A; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Bale S; Northwestern Scleroderma Program, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA., Marangoni RG; Northwestern Scleroderma Program, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Horbinski C; Department of Neurological Surgery.; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Miller SD; Department of Microbiology-Immunology and., Varga J; Northwestern Scleroderma Program, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. |
| Abstrakt: |
Systemic sclerosis (SSc) is a chronic, multisystem orphan disease with a highly variable clinical course, high mortality rate, and a poorly understood complex pathogenesis. We have identified an important role for a subpopulation of monocytes and macrophages characterized by surface expression of the scavenger receptor macrophage receptor with collagenous structure (MARCO) in chronic inflammation and fibrosis in SSc and in preclinical disease models. We show that MARCO+ monocytes and macrophages accumulate in lesional skin and lung in topographic proximity to activated myofibroblasts in patients with SSc and in the bleomycin-induced mouse model of SSc. Short-term treatment of mice with a potentially novel nanoparticle, poly(lactic-co-glycolic) acid (PLG), which is composed of a carboxylated, FDA-approved, biodegradable polymer and modulates activation and trafficking of MARCO+ inflammatory monocytes, markedly attenuated bleomycin-induced skin and lung inflammation and fibrosis. Mechanistically, in isolated cells in culture, PLG nanoparticles inhibited TGF-dependent fibrotic responses in vitro. Thus, MARCO+ monocytes are potent effector cells of skin and lung fibrosis and can be therapeutically targeted in SSc using PLG nanoparticles. |
