title: Macrophage-derived reactive oxygen species protects against autoimmune priming with a defined polymeric adjuvant.
abstract: Understanding the nature of adjuvants and the immune priming events in autoimmune diseases, such as rheumatoid arthritis, is a key challenge to identify their aetiology. Adjuvants are, however, complex structures with inflammatory and immune priming properties. Synthetic polymers provide a possibility to separate these functions and allow studies of the priming mechanisms in vivo. A well-balanced polymer, poly-N-isopropyl acrylamide (PNiPAAm) mixed with collagen type II (CII) induced relatively stronger autoimmunity and arthritis compared with more hydrophilic (polyacrylamide) or hydrophobic (poly-N-isopropylacrylamide-co-poly-N-tertbutylacrylamide and poly-N-tertbutylacrylamide) polymers. Clearly, all the synthesized polymers except the more hydrophobic poly-N-tertbutylacrylamide induced arthritis, especially in Ncf1-deficient mice, which are deficient in reactive oxygen species (ROS) production. We identified macrophages as the major infiltrating cells present at PNiPAAm-CII injection sites and demonstrate that ROS produced by the macrophages attenuated the immune response and the development of arthritis. Our results reveal that thermo-responsive polymers with high immune priming capacity could trigger an autoimmune response to CII and the subsequent arthritis development, in particular in the absence of NOX2 derived ROS. Importantly, ROS from macrophages protected against the autoimmune priming, demonstrating a critical regulatory role of macrophages in immune priming events.
authors.affiliation: Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.|Department of Chemical Engineering, Texas Tech University, Lubbock, TX, USA.
authors.forename: Akhilesh Kumar
authors.initials: AK
authors.lastname: Shakya
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.|Section for Medical Inflammation Research, Southern Medical University, Guangzhou, China.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.affiliation: Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.|Adjunct Faculty of University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Kutty Selva
authors.initials: KS
authors.lastname: Nandakumar
mesh_terms: D000178:Acrylamides; D000180:Acrylic Resins; D000276:Adjuvants, Immunologic; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D015551:Autoimmunity; D002478:Cells, Cultured; D024043:Collagen Type II; D005620:Freund's Adjuvant; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D000178:Acrylamides; D000180:Acrylic Resins; D000276:Adjuvants, Immunologic; D024043:Collagen Type II; D017382:Reactive Oxygen Species; C000608010:poly-N-tertbutylacrylamide; C079805:poly(N-isopropylacrylamide-N-tert-butylacrylamide)copolymer; C052970:poly-N-isopropylacrylamide; D005620:Freund's Adjuvant; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
keywords: adjuvant; arthritis; collagen type II; macrophages; poly-N-isopropylacrylamide