title: Activation of an immune-regulatory macrophage response and inhibition of lung inflammation in a mouse model of COPD using heat-shock protein alpha B-crystallin-loaded PLGA microparticles.
abstract: As an extracellular protein, the small heat-shock protein alpha B-crystallin (HSPB5) has anti-inflammatory effects in several mouse models of inflammation. Here, we show that these effects are associated with the ability of HSPB5 to activate an immune-regulatory response in macrophages via endosomal/phagosomal CD14 and Toll-like receptors 1 and 2. Humans, however, possess natural antibodies against HSPB5 that block receptor binding. To protect it from these antibodies, we encapsulated HSPB5 in porous PLGA microparticles. We document here size, morphology, protein loading and release characteristics of such microparticles. Apart from effectively protecting HSPB5 from neutralization, PLGA microparticles also strongly promoted macrophage targeting of HSPB via phagocytosis. As a result, HSPB5 in porous PLGA microparticles was more than 100-fold more effective in activating macrophages than free soluble protein. Yet, the immune-regulatory nature of the macrophage response, as documented here by microarray transcript profiling, remained the same. In mice developing cigarette smoke-induced COPD, HSPB5-loaded PLGA microparticles were selectively taken up by alveolar macrophages upon intratracheal administration, and significantly suppressed lung infiltration by lymphocytes and neutrophils. In contrast, 30-fold higher doses of free soluble HSPB5 remained ineffective. Our data indicate that porous HSPB5-PLGA microparticles hold considerable promise as an anti-inflammatory biomaterial for humans.
authors.affiliation: Delta Crystallon BV, Zernikedreef 9, Leiden, The Netherlands. hans@deltacrystallon.com
authors.forename: Johannes M
authors.initials: JM
authors.lastname: van Noort
authors.forename: Malika
authors.initials: M
authors.lastname: Bsibsi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nacken
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Gerritsen
authors.forename: Sandra
authors.initials: S
authors.lastname: Amor
authors.forename: Inge R
authors.initials: IR
authors.lastname: Holtman
authors.forename: Erik
authors.initials: E
authors.lastname: Boddeke
authors.forename: Ingrid
authors.initials: I
authors.lastname: van Ark
authors.forename: Thea
authors.initials: T
authors.lastname: Leusink-Muis
authors.forename: Gert
authors.initials: G
authors.lastname: Folkerts
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.forename: Maryam
authors.initials: M
authors.lastname: Amidi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry; D050888:Heat-Shock Proteins, Small / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008168:Lung / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications*; D051194:Toll-Like Receptor 1 / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D038203:alpha-Crystallin B Chain / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D050888:Heat-Shock Proteins, Small; D018950:Lipopolysaccharide Receptors; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D038203:alpha-Crystallin B Chain; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid