Investigation into Mechanisms NLRP3 Activation by Nickel Associated Multi-Walled

Summary

Principal Investigator: TERI ALYN GIRTSMAN
Abstract: DESCRIPTION (provided by applicant): Certain engineered nanomaterials (ENM) have been shown to cause significant lung pathological changes in animal models raising concern that human health effects will emerge with increasing use and exposure. However, a mechanistic predictive model based on physical and surface properties of ENM has not been established to aid in protecting human health. Other work in our laboratory has shown an association between in vitro NLRP3 inflammasome (NLRP3) activation and in vivo inflammation. In preliminary data, we have shown that there may be a correlation between the ability of nickel associated MWCNT (Ni-MWCNT) to activate NLRP3 in vitro using primary alveolar macrophages (AM) or THP-1 cells with lung inflammation and pathology. Therefore, we propose that in vitro activation of NLRP3 appears to be a reliable predictor of lung inflammation. The basis for the distinction between bioactive and benign ENM is most likely associated with the ability of ENM to be phagocytosed and/or ability to disrupt lysosomes causing cathepsin B release. We hypothesize that the in vivo inflammatory potential of ENM correlates well with lysosomal disrupting activity and NLRP3 activation. Based on preliminary data we propose that the inflammatory potential of MWCNT will be dependent on the amount of associated nickel. Therefore, our aims are: 1. Determine the relationship between NLRP3 inflammasome activity in AM and lung pathology in mice following exposure to defined and well- characterized Ni-MWCNT. 2. Determine the importance of Ni-MWCNT surface properties (amount of Nickel and surface charge) to cause cytotoxicity and degree of activation of the NLRP3 inflammasome using THP-1 cells. Finally, we will establish that internalization of MWCNT-Ni followed by lysosomal membrane disruption and Cathepsin B release is the initiating event in activation of the NLRP3 inflammasome. Thus, information from this study will be important in determining characteristics of safe ENM and establish mechanisms of action and may lead to an in vitro screening platform using THP-1 cells.
Funding Period: 2011-08-15 - 2014-08-14
more information: NIH RePORT

Top Publications

  1. pmc IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung
    Celine A Beamer
    Department of Biomedical and Pharmaceutical Sciences, Center for Environmental Health Sciences, The University of Montana, Missoula, MT 59812 1552, USA
    Nanotoxicology 7:1070-81. 2013
  2. pmc IL-1R signalling is critical for regulation of multi-walled carbon nanotubes-induced acute lung inflammation in C57Bl/6 mice
    TERI ALYN GIRTSMAN
    University of Montana, Department of Biomedical and Pharmaceutical Sciences, Center for Environmental Sciences, 32 Campus Drive, Missoula, MT, USA
    Nanotoxicology 8:17-27. 2014

Detail Information

Publications2

  1. pmc IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung
    Celine A Beamer
    Department of Biomedical and Pharmaceutical Sciences, Center for Environmental Health Sciences, The University of Montana, Missoula, MT 59812 1552, USA
    Nanotoxicology 7:1070-81. 2013
    ..Collectively, our data suggest that MWCNT induce epithelial damage that results in release of IL-33, which in turn promotes innate lymphoid cell recruitment and the development of IL-13-dependent inflammatory response...
  2. pmc IL-1R signalling is critical for regulation of multi-walled carbon nanotubes-induced acute lung inflammation in C57Bl/6 mice
    TERI ALYN GIRTSMAN
    University of Montana, Department of Biomedical and Pharmaceutical Sciences, Center for Environmental Sciences, 32 Campus Drive, Missoula, MT, USA
    Nanotoxicology 8:17-27. 2014
    ..These data suggest that IL-1R signalling plays a crucial role in the regulation of MWCNT-induced pulmonary inflammation...

Research Grants30

  1. Linking the physical and chemical characteristics of Qdots to their toxicity
    TERRANCE JAMES KAVANAGH; Fiscal Year: 2013
    ..These advances can then be used in safe design and manufacturing of nanomaterials so as to maximize their utility for many applications. ..
  2. Respiratory Effects of Silver and Carbon Nanomaterials (RESAC)
    Junfeng Zhang; Fiscal Year: 2013
    ..Our new models will mathematically link specific ENM properties (e.g., surface area) to biological effects, allowing the use of most relevant 'dosimetry'in predicting ENM health risks. ..
  3. Integrating Structive Activity, Biokinetics and Response for ENP Risk Assessment
    Brian D Thrall; Fiscal Year: 2013
    ....
  4. Genomics of Kidney Transplantation Admin
    Arthur J Matas; Fiscal Year: 2013
    ..The Administrative Core will also facilitate interaction between Sites, Cores, and Projects. ..
  5. Center for Nanobiology and Predictive Toxicology
    ANDRE ELIAS NEL; Fiscal Year: 2013
    ....
  6. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  7. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  8. Gulf Coast Health Alliance: health Risks related to the Macondo Spill (GC-HARMS)
    CORNELIS JOHAN ELFERINK; Fiscal Year: 2013
    ..Additionally, the consortium leverages support from two NIEHS P30 Core Centers to provide essential resources. ..
  9. Effects of nanoparticle dispersion status on bioactivity and translocation in the
    TINA MARIE SAGER; Fiscal Year: 2013
    ..Namely the highly debated question of whether dispersion status of the nanoparticle suspension (pre-exposure) is of importance, will be answered in the proposed studies. ..
  10. EPIDEMIOLOGY OF ALCOHOL PROBLEMS
    Thomas K Greenfield; Fiscal Year: 2013
    ..We plan to build research capacity in the Center and other organizations, enhance careers of new investigators, and make key findings accessible to researchers, policy makers, practitioners, and the public. ..
  11. Novel Polymeric nanoparticles for drug delivery applications
    Anthony J McGoron; Fiscal Year: 2013
    ....
  12. Nanoparticle properties and alveolar epithelial barrier/transport functions
    EDWARD DAVID CRANDALL; Fiscal Year: 2013
    ..g., pulmonary drug/gene delivery). ..
  13. Engineered Nanomaterials: Linking Physical and Chemical Properties to Biology
    KENT ED PINKERTON; Fiscal Year: 2013
    ..The goal of Project 2 is to define exposure effects of high aspect ratio nanomaterials (single walled carbon nanotubes and nanowires) in an in vivo inhalation model that includes airways hyperresonsiveness...