TY - JOUR
T1 - PLG nanoparticles target fibroblasts and MARCO+ monocytes to reverse multiorgan fibrosis
AU - Xu, Dan
AU - Bhattacharyya, Swati
AU - Wang, Wenxia
AU - Ifergan, Igal
AU - Wong, Ming Yi Alice Chiang
AU - Procissi, Daniele
AU - Yeldandi, Anjana
AU - Bale, Swarna
AU - Marangoni, Roberta Goncalves
AU - Horbinski, Craig
AU - Miller, Stephen D.
AU - Varga, John
N1 - Funding Information:
This work was supported by grants from the NIH (1 R21 AR073371 to SDM and JV) and the National Scleroderma Foundation (research grant to DX). We gratefully acknowledge Mary Carns and Kathleen Aren for technical assistance, as well as the Northwestern Mouse Histopathology & Phenotyping Core, Pathology Core, Cancer Center Flow Cytometry Core, and Nikon Imaging Center and Small Animal Imaging Facility Core for their services. We acknowledge the unreserved support from all members of the Miller and Varga laboratories. Illustrations were created using Biorender.com.
Publisher Copyright:
© 2022, Xu et al.
PY - 2022/3/8
Y1 - 2022/3/8
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.151037
DO - 10.1172/jci.insight.151037
M3 - Article
C2 - 35104243
AN - SCOPUS:85125891820
SN - 2379-3708
VL - 7
JO - JCI Insight
JF - JCI Insight
IS - 5
M1 - e151037
ER -