title: The NLRP3 inflammasome is dispensable for ER stress-induced pancreatic β-cell damage in Akita mice.
abstract: Uncontrolled endoplasmic reticulum (ER) stress activates members of the NOD-like receptor family, which are involved in the pyrin domain containing 3 (NLRP3) inflammasome pathway. This pathway has been proposed to contribute to β-cell dysfunction and death. However, the connection between ER stress and NLRP3 inflammasome activation remains controversial. Here we generated Akita/KO (Ins2(+/C96Y); NLRP3(-/-)) mice by crossing Akita (Ins2(+/C96Y); NLRP3(+/+)) mice with NLRP3 KO (Ins2(+/+); NLRP3(-/-)) mice. We then compared the metabolic phenotypes of the different strains. Knockout of the NLRP3 inflammasome did not affect the onset or the severity of diabetes in Akita/KO mice at any point of the study. Histological observations of pancreatic islets supported these findings. Tunicamycin-exposed islets from NLRP3 KO mice exhibited similar levels of ER stress and apoptosis induction as islets from WT (Ins2(+/+); NLRP3(+/+)) mice. Furthermore, NLRP3 deletion did not prevent tunicamycin-mediated reduction of glucose-stimulated insulin secretion. In conclusion, deletion of the NLRP3 inflammasome did not protect against ER stress-induced diabetes development or β-cell damage, indicating that β cell death in Akita mice is not mediated via activation of the NLRP3 inflammasome.
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896, Republic of Korea.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896, Republic of Korea.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Song
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi 14662, Republic of Korea.
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Preventive Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896, Republic of Korea.
authors.forename: Keun Sang
authors.initials: KS
authors.lastname: Kwon
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896, Republic of Korea. Electronic address: bhpark@jbnu.ac.kr.
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D058847:Inflammasomes; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D011489:Protein Denaturation; D014415:Tunicamycin / Q000737:chemistry
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D007328:Insulin; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014415:Tunicamycin; D005947:Glucose
keywords: Akita; ER stress; Islets; NLRP3 inflammasome; Tunicamycin