Activation of An Immune-Regulatory Macrophage Response and Inhibition of Lung Inflammation in A Mouse Model of COPD Using Porous Alpha B-crystallin-Loaded PLGA Microparticles

J. M. van Noort1, M. Bsibsi1, P. J. Nacken1, W. H. Gerritsen2, S. Amor2, 3, I. R. Holtman4, E. Boddeke4, I. van Ark5, T. Leusink-Muis5, G. Folkerts5, W. E. Hennink6, M. Amidi6

1Delta Crystallon BV, Zernikedreef 9, 2333 CK Leiden, The Netherlands; 2Department of Pathology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands; 3Department of Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, E1 2AT London, United Kingdom; 4Department of Medical Physiology, University Medical Centre Groningen, 9713 AV Groningen, The Netherlands; 5Division of Pharmacology, Institute for Pharmaceutical Sciences, University Utrecht, 3508 TB Utrecht, The Netherlands; 6Department of Pharmaceutics, Institute for Pharmaceutical Sciences, University Utrecht, 3508 TB Utrecht, The Netherlands

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Summary
As an extracellular protein, the small heat-shock protein alpha B-crystallin (HSPB5) has antiinflammatory effects in several mouse models of inflammation. The anti inflammatory effects of HSPB5 are associated with the ability of the protein to activate an immune-regulatory response in macrophages via endosomal/phagosomal CD14 and Toll-like receptors (TLR) 1 & 2. Humans, however, possess natural antibodies against HSPB5 that block receptor binding. Here we show that only porous HSPB5-loaded PLGA microparticles are able to protect HSPB5 from the neutralizing antibodies and substantially promote macrophage targeting via phagocytosis. Here, we show that intratracheal administration of HSPB5-PLGA microparticles in COPD mice strongly suppresses lung inflammation.

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