Regulation of the Profibrotic Mechanisms of MACRO+ Myeloid Cells in Scleroderma

Project: Research project

Description

It is estimated that scleroderma affects about 300,000 Americans, predominantly women. It is a progressive and untreatable disease of unknown cause and high mortality. No therapy to date has been shown to significantly alter survival but only alleviate the pain. The pathogenesis of scleroderma is characterized by overt inflammation followed by progressive tissue damage and fibrosis secondary to excessive production of collagen and accumulation of myofibroblasts in lesional tissues causing organ failure. Recent genomic studies have revealed potential pathogenic role of inflammatory myeloid cells, including inflammatory monocytes (ϕIMs) and macrophages (Ms). We have shown for the first time accumulation of MARCO+ ϕIMs and Ms within the lesional skin and lung of scleroderma patients and mice with bleomycin-induced scleroderma. MARCO is a type II glycoprotein scavenger receptor expressed by activated phagocytic antigen presenting cellsand is linked to alternate (M2) activation of Ms, resulting in pro-fibrotic activities. The function and pathological contribution of MARCO+ ϕIMs and Ms and the therapeutic potential of targeting these cells in scleroderma have never been addressed. We pioneered an innovative strategy targeting ϕIMs and Ms by leveraging the drug-like biological properties of carboxylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles. We showed that negatively-charged 500 nM diameter PLGA particles are selectively recognized and bound by ϕIMs and Ms via MARCO. PLGA-associated ϕIMs/Ms undergo sequestration in the spleen and apoptosis, culminating in reduced immune pathology in bleomycin-treated mice. We hypothesize that PLGA nanoparticle can be used i) as a unique biological probe for illuminating the pathogenic roles of ϕIMs and Ms in scleroderma, and to ii) treat inflammation-driven fibrotic diseases. We will test this hypothesis in 3 aims: Aim 1 will measure MARCO levels to determine their clinical significance using skin biopsies from scleroderma patients and healthy controls. Aim 2 will evaluate the efficacy of MARCO-targeting PLGA nanoparticle treatment on progression and alleviation of fibrosis formation in the bleomycin murine model of scleroderma. Aim 3 will delineate mechanisms underlying the deregulated fibrogenic nature of MARCO+ ϕIMs and Ms in vitro. In summary, this application leverages exciting preliminary findings from the Miller and Varga labs implicating a pathologic role for MARCO+ ϕIMs and Ms in the pathogenesis of scleroderma and showing the potential ability to regulate their pro-fibrotic function using a cutting-edge and translationally-relevant nanoparticle approach. These studies under the co-direction of two well-established PIs benefit from their complementary expertise in inflammation, fibrosis and scleroderma research. The results should significantly advance our understanding of scleroderma by illuminating the pro-fibrotic mechanism(s) of action of MARCO+ ϕIMs and Ms, validating the feasibility of a novel therapeutic in preclinical scleroderma models, developing strategies for the identification of patients suitable for the MARCO-targeting therapy.
StatusActive
Effective start/end date6/1/185/31/20

Funding

  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (5R21AR073371-02)

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Myeloid Cells
Monocytes
Macrophages
Nanoparticles
Fibrosis
Inflammation
Therapeutics
Scavenger Receptors
Skin
Myofibroblasts
Macrophage Activation
Bleomycin
Glycoproteins
Collagen
Spleen
polylactic acid-polyglycolic acid copolymer
Apoptosis
Pathology
Biopsy
Antigens