Research Paper Volume 11, Issue 23 pp 11659—11672

Nickel induces inflammatory activation via NF-κB, MAPKs, IRF3 and NLRP3 inflammasome signaling pathways in macrophages

Hongrui Guo 1, 2, *, , Huan Liu 1, *, , Zhijie Jian 1, *, , Hengmin Cui 1, 2, 3, , Jing Fang 1, 2, , Zhicai Zuo 1, 2, , Junliang Deng 1, 2, , Yinglun Li 1, 2, , Xun Wang 1, 2, , Ling Zhao 1, 2, , Yi Geng 1, , Ping Ouyang 1, , Weiming Lai 1, , Zhengli Chen 1, , Chao Huang 1, ,

  • 1 College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
  • 2 Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
  • 3 Key Laboratory of Agricultural Information Engineering of Sichuan Province, Sichuan Agriculture University, Yaan, Sichuan 625014, China
* Equal contribution

received: October 11, 2019 ; accepted: November 23, 2019 ; published: December 10, 2019 ;
How to Cite

Copyright © 2019 Guo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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 NiCl2 activated nuclear factor kappa B (NF-κB), 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-1β (IL-1β), -6, -8, -18, tumor necrosis factor-α (TNF-α) and interferon β (INF-β). We also found that nickel chloride (NiCl2) activated Nod-like receptor 3 (NLRP3) inflammasome pathway, resulting in the proteolytic cleavage and release of IL-1β. NiCl2 induced the accumulation of mitochondrial reactive oxygen species (mtROS) and the release of mitochondrial DNA (mtDNA), thus activating NLRP3 inflammasome pathway. Additionally, NiCl2-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 NiCl2 induces inflammatory activation in BMDMs via NF-κB, 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.


NiCl2: nickel chloride; BMDMs: bone marrow-derived macrophages; NF-κB: nuclear factor kappa B; MAPKs: mitogen-activated protein kinases; IRF3: interferon regulatory factor 3; IL-1β: interleukin-1β; TNF-α: tumor necrosis factor-α; INF-β: interferon β; mtROS: mitochondrial reactive oxygen species; mtDNA: mitochondrial DNA; JNK: Jun amino-terminal kinases; ERK: extracellular signal-regulated kinase; NLRP3: Nod-like receptor 3; ASC: apoptosis-associated speck-like protein containing CARD.