TY - JOUR
T1 - Therapeutic inflammatory monocyte modulation using immune-modifying microparticles
AU - Getts, Daniel R.
AU - Terry, Rachael L.
AU - Getts, Meghann Teague
AU - Deffrasnes, Celine
AU - Müller, Marcus
AU - Vreden, Carynvan
AU - Ashhurst, Thomas M.
AU - Chami, Belal
AU - McCarthy, Derrick
AU - Wu, Huiling
AU - Jin, Ma
AU - Martin, Aaron
AU - Shae, Lonnie D.
AU - Witting, Paul
AU - Kansas, Geoffrey Scott
AU - Kühn, Joachim
AU - Hafezi, Wali
AU - Campbell, Iain L.
AU - Reilly, David
AU - Say, Jana
AU - Brown, Louise
AU - White, Melanie Y.
AU - Cordwell, Stuart J.
AU - Chadban, Steven J.
AU - Thorp, Edward Benjamin
AU - Bao, Shisan
AU - Miller, Stephen D
AU - King, Nicholas J.C.
PY - 2014/1/15
Y1 - 2014/1/15
N2 - Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3-mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate-induced colitis, thioglycollate- induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.
AB - Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3-mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate-induced colitis, thioglycollate- induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.
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U2 - 10.1126/scitranslmed.3007563
DO - 10.1126/scitranslmed.3007563
M3 - Article
C2 - 24431111
AN - SCOPUS:84893364090
SN - 1946-6234
VL - 6
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 219
M1 - 219ra7
ER -