title: DAMP production by human islets under low oxygen and nutrients in the presence or absence of an immunoisolating-capsule and necrostatin-1.
abstract: In between the period of transplantation and revascularization, pancreatic islets are exposed to low-oxygen and low-nutrient conditions. In the present study we mimicked those conditions in vitro to study the involvement of different cell death processes, release of danger-associated molecular patterns (DAMP), and associated in vitro immune activation. Under low-oxygen and low-nutrient conditions, apoptosis, autophagy and necroptosis occur in human islets. Necroptosis is responsible for DAMP-release such as dsDNA, uric acid, and HMGB1. The sensors of the innate immune system able to recognize these DAMPs are mainly TLR, NOD receptors, and C-type lectins. By using cell-lines with a non-functional adaptor molecule MyD88, we were able to show that the islet-derived DAMPs signal mainly via TLR. Immunoisolation in immunoprotective membranes reduced DAMP release and immune activation via retention of the relative large DAMPs in the capsules. Another effective strategy was suppressing necroptosis using the inhibitor nec-1. Although the effect on cell-survival was minor, nec-1 was able to reduce the release of HMGB1 and its associated immune activation. Our data demonstrate that in the immediate post-transplant period islets release DAMPs that in vitro enhance responses of innate immune cells. DAMP release can be reduced in vitro by immunoisolation or intervention with nec-1.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Section of Immunoendocrinology, Groningen, 9713 GZ, The Netherlands.
authors.forename: Genaro A
authors.initials: GA
authors.lastname: Paredes-Juarez
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Section of Immunoendocrinology, Groningen, 9713 GZ, The Netherlands.
authors.forename: Neha M
authors.initials: NM
authors.lastname: Sahasrabudhe
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Section of Immunoendocrinology, Groningen, 9713 GZ, The Netherlands.
authors.forename: Reina S
authors.initials: RS
authors.lastname: Tjoelker
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Section of Immunoendocrinology, Groningen, 9713 GZ, The Netherlands.
authors.forename: Bart J
authors.initials: BJ
authors.lastname: de Haan
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
authors.forename: Marten A
authors.initials: MA
authors.lastname: Engelse
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
authors.forename: Eelco J P
authors.initials: EJP
authors.lastname: de Koning
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Section of Immunoendocrinology, Groningen, 9713 GZ, The Netherlands.
authors.forename: Marijke M
authors.initials: MM
authors.lastname: Faas
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Section of Immunoendocrinology, Groningen, 9713 GZ, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: de Vos
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001343:Autophagy / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D056747:Immunomodulation; D007211:Indoles / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D007093:Imidazoles; D007211:Indoles; D051193:Toll-Like Receptors; C507699:necrostatin-1; D010100:Oxygen