Abstract
Rationale: Despite advances in symptomatic management, the pathogenesis of SSc remains incompletely understood and there are no effective treatments. Our findings implicate an inflammatory monocyte subset expressing the scavenger receptor MARCO (MAcrophage Receptor with COllagenous structure), as an important mediator of chronic inflammation in SSc patients and murine disease models. We hypothesize that MARCO+ inflammatory monocytes (φIMs) and macrophages (MΦs) play a key pathogenic role in SSc by promoting the development and/or hindering the resolution, of skin fibrosis. We recently developed an innovative biodegradable immunomodulatory nanoparticles (IMP) made of FDA-approved biopolymer poly(lactic-co-glycolic acid) (PLGA) that regulates the trafficking and function of φIMs and MΦs. Results: We provide the first evidence that MARCO+ φIMs/MΦs accumulate in lesional skin and lung in SSc patients in topographic proximity to activated myofibroblasts. To evalute the role of MARCO+ φIMs/MΦs, we gave a short course of IMP treatment at disease onset using a subcutaneous bleomycin-induced mouse model of inflammatory SSc with lung and skin fibrotic phenotype. IMP treatment significantly reduced skin infiltration of professional antigen presenting cells (APC) including MARCO+ φIMs, MΦs, and myeloid dendritic cells (mDC). The activation of these APC was also reduced. Significantly, IMP treatment ameliorates skin fibrosis evaluated by histological analysis. Conclusions: These data showed for the first time that immune-modulating biodegradable PLG nanoparticles given at onset improved outcomes at the acute phase in a well-accepted mouse inflammatory model of skin fibrosis. Modulation of fibrosis is most likely exerted through dampening overt immune responses in the skin, while promoting establishment of homeostasis of myofibroblast. Regulation of systemic fibrosis at locations distal to injection site by IMP merits further investigation.
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