Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells

Souvarish Sarkar, Dharmin Rokad, Emir Malovic, Jie Luo, Dilshan S. Harischandra, Huajun Jin, Vellareddy Anantharam, Xuemei Huang, Mechelle Lewis, Arthi Kanthasamy, Anumantha G. Kanthasamy

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn 2+ ) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn 2+ activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn 2+ substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1 (IL-1). Exposure of mice to Mn 2+ had similar effects in brain microglial cells. Furthermore, Mn 2+ impaired mitochondrial ATP generation, basal respiratory rate, and spare capacity in microglial cells. These data suggest that Mn-induced mitochondrial defects drove the inflammasome signal amplification. We found that Mn induced cell-to-cell transfer of the inflammasome adaptor protein ASC in exosomes. Furthermore, primed microglial cells exposed to exosomes from Mn-treated mice released more IL-1 than did cells exposed to exosomes from control-treated animals. We also observed that welders exposed to manganese-containing fumes had plasma exosomes that contained more ASC than did those from a matched control group. Together, these results suggest that the divalent metal manganese acts as a key amplifier of NLRP3 inflammasome signaling and exosomal ASC release.

Original languageEnglish (US)
Article numberaat9900
JournalScience Signaling
Volume12
Issue number563
DOIs
StatePublished - Jan 8 2019

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Inflammasomes
Manganese
Exosomes
Interleukin-1
Neurodegenerative diseases
Caspase 1
Fumes
Amplification
Brain
Animals
Inflammation
Adenosine Triphosphate
Metals
Cytokines
Plasmas
Defects
Respiratory Rate
Neurodegenerative Diseases
Research Design
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Sarkar, S., Rokad, D., Malovic, E., Luo, J., Harischandra, D. S., Jin, H., ... Kanthasamy, A. G. (2019). Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells. Science Signaling, 12(563), [aat9900]. https://doi.org/10.1126/scisignal.aat9900
Sarkar, Souvarish ; Rokad, Dharmin ; Malovic, Emir ; Luo, Jie ; Harischandra, Dilshan S. ; Jin, Huajun ; Anantharam, Vellareddy ; Huang, Xuemei ; Lewis, Mechelle ; Kanthasamy, Arthi ; Kanthasamy, Anumantha G. / Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells. In: Science Signaling. 2019 ; Vol. 12, No. 563.
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abstract = "Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn 2+ ) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn 2+ activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn 2+ substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1 (IL-1). Exposure of mice to Mn 2+ had similar effects in brain microglial cells. Furthermore, Mn 2+ impaired mitochondrial ATP generation, basal respiratory rate, and spare capacity in microglial cells. These data suggest that Mn-induced mitochondrial defects drove the inflammasome signal amplification. We found that Mn induced cell-to-cell transfer of the inflammasome adaptor protein ASC in exosomes. Furthermore, primed microglial cells exposed to exosomes from Mn-treated mice released more IL-1 than did cells exposed to exosomes from control-treated animals. We also observed that welders exposed to manganese-containing fumes had plasma exosomes that contained more ASC than did those from a matched control group. Together, these results suggest that the divalent metal manganese acts as a key amplifier of NLRP3 inflammasome signaling and exosomal ASC release.",
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Sarkar, S, Rokad, D, Malovic, E, Luo, J, Harischandra, DS, Jin, H, Anantharam, V, Huang, X, Lewis, M, Kanthasamy, A & Kanthasamy, AG 2019, 'Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells', Science Signaling, vol. 12, no. 563, aat9900. https://doi.org/10.1126/scisignal.aat9900

Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells. / Sarkar, Souvarish; Rokad, Dharmin; Malovic, Emir; Luo, Jie; Harischandra, Dilshan S.; Jin, Huajun; Anantharam, Vellareddy; Huang, Xuemei; Lewis, Mechelle; Kanthasamy, Arthi; Kanthasamy, Anumantha G.

In: Science Signaling, Vol. 12, No. 563, aat9900, 08.01.2019.

Research output: Contribution to journalArticle

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AU - Sarkar, Souvarish

AU - Rokad, Dharmin

AU - Malovic, Emir

AU - Luo, Jie

AU - Harischandra, Dilshan S.

AU - Jin, Huajun

AU - Anantharam, Vellareddy

AU - Huang, Xuemei

AU - Lewis, Mechelle

AU - Kanthasamy, Arthi

AU - Kanthasamy, Anumantha G.

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N2 - Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn 2+ ) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn 2+ activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn 2+ substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1 (IL-1). Exposure of mice to Mn 2+ had similar effects in brain microglial cells. Furthermore, Mn 2+ impaired mitochondrial ATP generation, basal respiratory rate, and spare capacity in microglial cells. These data suggest that Mn-induced mitochondrial defects drove the inflammasome signal amplification. We found that Mn induced cell-to-cell transfer of the inflammasome adaptor protein ASC in exosomes. Furthermore, primed microglial cells exposed to exosomes from Mn-treated mice released more IL-1 than did cells exposed to exosomes from control-treated animals. We also observed that welders exposed to manganese-containing fumes had plasma exosomes that contained more ASC than did those from a matched control group. Together, these results suggest that the divalent metal manganese acts as a key amplifier of NLRP3 inflammasome signaling and exosomal ASC release.

AB - Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn 2+ ) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn 2+ activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn 2+ substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1 (IL-1). Exposure of mice to Mn 2+ had similar effects in brain microglial cells. Furthermore, Mn 2+ impaired mitochondrial ATP generation, basal respiratory rate, and spare capacity in microglial cells. These data suggest that Mn-induced mitochondrial defects drove the inflammasome signal amplification. We found that Mn induced cell-to-cell transfer of the inflammasome adaptor protein ASC in exosomes. Furthermore, primed microglial cells exposed to exosomes from Mn-treated mice released more IL-1 than did cells exposed to exosomes from control-treated animals. We also observed that welders exposed to manganese-containing fumes had plasma exosomes that contained more ASC than did those from a matched control group. Together, these results suggest that the divalent metal manganese acts as a key amplifier of NLRP3 inflammasome signaling and exosomal ASC release.

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