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

Dan Xu, Swati Bhattacharyya, Wenxia Wang, Igal Ifergan, Ming Yi Alice Chiang Wong, Daniele Procissi, Anjana Yeldandi, Swarna Bale, Roberta Goncalves Marangoni, Craig Horbinski, Stephen D. Miller*, John Varga

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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 bleomycininduced 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.

Original languageEnglish (US)
Article numbere151037
JournalJCI Insight
Volume7
Issue number5
DOIs
StatePublished - Mar 8 2022

ASJC Scopus subject areas

  • Medicine(all)

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