PMID- 31822637 OWN - NLM STAT- MEDLINE DCOM- 20201023 LR - 20201023 IS - 1945-4589 (Electronic) IS - 1945-4589 (Linking) VI - 11 IP - 23 DP - 2019 Dec 10 TI - Nickel induces inflammatory activation via NF-kappaB, MAPKs, IRF3 and NLRP3 inflammasome signaling pathways in macrophages. PG - 11659-11672 LID - 10.18632/aging.102570 [doi] AB - Nickel (Ni), an environmental hazard, widely causes allergic contact hypersensitivity worldwide. Despite that Ni-stimulated pro-inflammatory response is vital in allergy, the underlying molecular mechanisms remain largely unclear. Here, we demonstrated that NiCl(2) activated nuclear factor kappa B (NF-kappaB), mitogen-activated protein kinases (MAPKs) and interferon regulatory factor 3 (IRF3) signaling pathways in primary bone marrow-derived macrophages (BMDMs), leading to the altered transcription levels of interleukin-1beta (IL-1beta), -6, -8, -18, tumor necrosis factor-alpha (TNF-alpha) and interferon beta (INF-beta). We also found that nickel chloride (NiCl(2)) activated Nod-like receptor 3 (NLRP3) inflammasome pathway, resulting in the proteolytic cleavage and release of IL-1beta. NiCl(2) induced the accumulation of mitochondrial reactive oxygen species (mtROS) and the release of mitochondrial DNA (mtDNA), thus activating NLRP3 inflammasome pathway. Additionally, NiCl(2)-induced apoptosis was dependent on the generation of mtROS, and caspase-1 activation might also partly contribute to the apoptotic process. Altogether, abovementioned results indicate that NiCl(2) induces inflammatory activation in BMDMs via NF-kappaB, MAPKs, IRF3 signaling pathways as well as NLRP3 inflammasome pathway, which provides a mechanism to improve the efficiency of treatment against Ni-induced allergic reactions. FAU - Guo, Hongrui AU - Guo H AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. AD - Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China. FAU - Liu, Huan AU - Liu H AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. FAU - Jian, Zhijie AU - Jian Z AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. FAU - Cui, Hengmin AU - Cui H AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. AD - Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China. AD - Key Laboratory of Agricultural Information Engineering of Sichuan Province, Sichuan Agriculture University, Yaan, Sichuan 625014, China. FAU - Fang, Jing AU - Fang J AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. AD - Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China. FAU - Zuo, Zhicai AU - Zuo Z AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. AD - Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China. FAU - Deng, Junliang AU - Deng J AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. AD - Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China. FAU - Li, Yinglun AU - Li Y AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. AD - Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China. FAU - Wang, Xun AU - Wang X AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. AD - Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China. FAU - Zhao, Ling AU - Zhao L AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. AD - Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China. FAU - Geng, Yi AU - Geng Y AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. FAU - Ouyang, Ping AU - Ouyang P AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. FAU - Lai, Weiming AU - Lai W AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. FAU - Chen, Zhengli AU - Chen Z AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. FAU - Huang, Chao AU - Huang C AD - College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191210 PL - United States TA - Aging (Albany NY) JT - Aging JID - 101508617 RN - 0 (Environmental Pollutants) RN - 0 (Interferon Regulatory Factor-3) RN - 0 (Irf3 protein, mouse) RN - 0 (NF-kappa B) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Reactive Oxygen Species) RN - 7OV03QG267 (Nickel) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) SB - IM MH - Animals MH - Apoptosis MH - Cell Survival/drug effects MH - Environmental Pollutants MH - Gene Expression Regulation/drug effects MH - Humans MH - Inflammation/*chemically induced/metabolism MH - Interferon Regulatory Factor-3/genetics/*metabolism MH - Macrophages/*drug effects/metabolism MH - Membrane Potential, Mitochondrial MH - Mice MH - Mitochondria/drug effects/physiology MH - Mitogen-Activated Protein Kinase Kinases/genetics/*metabolism MH - NF-kappa B/*metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism MH - Nickel/*pharmacology MH - Reactive Oxygen Species PMC - PMC6932914 OTO - NOTNLM OT - BMDMs OT - NF-kappaB OT - NiCl2 OT - apoptosis OT - inflammasome COIS- CONFLICTS OF INTEREST: The authors declare that there are no conflicts of interest. EDAT- 2019/12/12 06:00 MHDA- 2020/10/24 06:00 PMCR- 2019/12/15 CRDT- 2019/12/12 06:00 PHST- 2019/10/11 00:00 [received] PHST- 2019/11/23 00:00 [accepted] PHST- 2019/12/12 06:00 [pubmed] PHST- 2020/10/24 06:00 [medline] PHST- 2019/12/12 06:00 [entrez] PHST- 2019/12/15 00:00 [pmc-release] AID - 102570 [pii] AID - 10.18632/aging.102570 [doi] PST - ppublish SO - Aging (Albany NY). 2019 Dec 10;11(23):11659-11672. doi: 10.18632/aging.102570. Epub 2019 Dec 10.