The role of pathogen-associated molecular patterns in inflammatory responses against alginate based microcapsules.
Alginate-based microcapsules are used for immunoisolation of cells to release therapeutics on a minute-to-minute basis. Unfortunately, alginate-based microcapsules are suffering from varying degrees of success, which is usually attributed to differences in tissue responses. This results in failure of the therapeutic cells. In the present study we show that commercial, crude alginates may contain pathogen-associated molecular patterns (PAMPs), which are recognized by the sensors of the innate immune system. Known sensors are Toll-like receptors (TLRs), NOD receptors, and C-type lectins. By using cell-lines with a non-functional adaptor molecule essential in Toll-like receptor signaling, i.e. MyD88, we were able to show that alginates signal mainly via MyD88. This was found for low-G, intermediate-G, and high-G alginates applied in calcium-beads, barium-beads as well as in alginate-PLL-alginate capsules. These alginates did stimulate TLRs 2, 5, 8, and 9 but not TLR4 (LPS receptor). Upon implantation in rats these alginates provoked a strong inflammatory response resulting in fibrosis of the capsules. Analysis demonstrated that commercial alginates contain the PAMPs peptidoglycan, lipoteichoic acid, and flagellin. By applying purification procedures, these PAMPs were largely removed. This was associated with deletion of the inflammatory tissue responses as confirmed by an implantation experiment in rats. Our data also show that alginate itself does not provoke TLR mediated responses. We were able to unravel the sensor mechanism by which contaminants in alginates may provoke inflammatory responses.
Department of Pathology and Medical Biology, Section of Immunoendocrinology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands. Electronic address: G.Paredes@umcg.nl.
Genaro A
GA
Paredes-Juarez
Bart J
BJ
de Haan
Marijke M
MM
Faas
Paul
P
de Vos
D000464:Alginates / Q000009:adverse effects*; D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects; D002214:Capsules; D004339:Drug Compounding; D005355:Fibrosis / Q000139:chemically induced / Q000276:immunology; D020723:Glucuronic Acid / Q000009:adverse effects / Q000276:immunology; D006603:Hexuronic Acids / Q000009:adverse effects / Q000276:immunology; D007113:Immunity, Innate; D007249:Inflammation / Q000139:chemically induced* / Q000276:immunology; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D019736:Prostheses and Implants; D051381:Rats; D051193:Toll-Like Receptors / Q000276:immunology*
D000464:Alginates; D001672:Biocompatible Materials; D002214:Capsules; D006603:Hexuronic Acids; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D020723:Glucuronic Acid
Alginate; Inflammation; Microencapsulation; Pathogen-associated molecular patterns; Therapeutic cells