PLG nanoparticles target fibroblasts and MARCO+ monocytes to reverse multiorgan fibrosis

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 th...

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Bibliographic Details
Published in:JCI insight 2022-03, Vol.7 (5)
Main Authors: Xu, Dan, Bhattacharyya, Swati, Wang, Wenxia, Ifergan, Igal, Wong, Ming-Yi Alice Chiang, Procissi, Daniele, Yeldandi, Anjana, Bale, Swarna, Marangoni, Roberta Goncalves, Horbinski, Craig, Miller, Stephen D, Varga, John
Format: Article
Language:English
Subjects:
Animals
Autoimmunity
Bleomycin - toxicity
Dermatology
Fibroblasts - metabolism
Fibrosis
Humans
Mice
Monocytes - metabolism
Nanoparticles
Receptors, Immunologic - metabolism
Scleroderma, Systemic - drug therapy
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Summary: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.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.151037